A protein that helps make neurons also works to reprogram scar tissue cells into heart muscle cells, especially in partnership with a second protein, according to a study led by Li Qian, PhD, at the UNC School of Medicine.

CHAPEL HILL, N.C. Scientists at the UNC School of Medicine have made a significant advance in the promising field of cellular reprogramming and organ regeneration, and the discovery could play a major role in future medicines to heal damaged hearts.

In a study published in the journal Cell Stem Cell, scientists at the University of North Carolina at Chapel Hill discovered a more streamlined and efficient method for reprogramming scar tissue cells (fibroblasts) to become healthy heart muscle cells (cardiomyocytes). Fibroblasts produce the fibrous, stiff tissue that contributes to heart failure after a heart attack or because of heart disease. Turning fibroblasts into cardiomyocytes is being investigated as a potential future strategy for treating or even someday curing this common and deadly condition.

Surprisingly, the key to the new cardiomyocyte-making technique turned out to be a gene activity-controlling protein called Ascl1, which is known to be a crucial protein involved in turning fibroblasts into neurons. Researchers had thought Ascl1 was neuron-specific.

Its an outside-the-box finding, and we expect it to be useful in developing future cardiac therapies and potentially other kinds of therapeutic cellular reprogramming, said study senior author Li Qian, PhD, associate professor in the UNC Department of Pathology and Lab Medicine and associate director of the McAllister Heart Institute at UNC School of Medicine.

Scientists over the last 15 years have developed various techniques to reprogram adult cells to become stem cells, then to induce those stem cells to become adult cells of some other type. More recently, scientists have been finding ways to do this reprogramming more directly straight from one mature cell type to another. The hope has been that when these methods are made maximally safe, effective, and efficient, doctors will be able to use a simple injection into patients to reprogram harm-causing cells into beneficial ones.

Reprogramming fibroblasts has long been one of the important goals in the field, Qian said. Fibroblast over-activity underlies many major diseases and conditions including heart failure, chronic obstructive pulmonary disease, liver disease, kidney disease, and the scar-like brain damage that occurs after strokes.

In the new study, Qians team, including co-first-authors Haofei Wang, PhD, a postdoctoral researcher, and MD/PhD student Benjamin Keepers, used three existing techniques to reprogram mouse fibroblasts into cardiomyocytes, liver cells, and neurons. Their aim was to catalogue and compare the changes in cells gene activity patterns and gene-activity regulation factors during these three distinct reprogrammings.

Unexpectedly, the researchers found that the reprogramming of fibroblasts into neurons activated a set of cardiomyocyte genes. Soon they determined that this activation was due to Ascl1, one of the master-programmer transcription factor proteins that had been used to make the neurons.

Since Ascl1 activated cardiomyocyte genes, the researchers added it to the three-transcription-factor cocktail they had been using for making cardiomyocytes, to see what would happen. They were astonished to find that it dramatically increased the efficiency of reprogramming the proportion of successfully reprogrammed cells by more than ten times. In fact, they found that they could now dispense with two of the three factors from their original cocktail, retaining only Ascl1 and another transcription factor called Mef2c.

In further experiments they found evidence that Ascl1 on its own activates both neuron and cardiomyocyte genes, but it shifts away from the pro-neuron role when accompanied by Mef2c. In synergy with Mef2c, Ascl1 switches on a broad set of cardiomyocyte genes.

Ascl1 and Mef2c work together to exert pro-cardiomyocyte effects that neither factor alone exerts, making for a potent reprogramming cocktail, Qian said.

The results show that the major transcription factors used in direct cellular reprogramming arent necessarily exclusive to one targeted cell type.

Perhaps more importantly, they represent another step on the path towards future cell-reprogramming therapies for major disorders. Qian says that she and her team hope to make a two-in-one synthetic protein that contains the effective bits of both Ascl1 and Mef2c, and could be injected into failing hearts to mend them.

Cross-lineage Potential of Ascl1 Uncovered by Comparing Diverse Reprogramming Regulatomes was co-authored by Haofei Wang, Benjamin Keepers, Yunzhe Qian, Yifang Xie, Marazzano Colon, Jiandong Liu, and Li Qian. Funding was provided by the American Heart Association and the National Institutes of Health (T32HL069768, F30HL154659, R35HL155656, R01HL139976, R01HL139880).

Media contact: Mark Derewicz, 919-923-0959

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Scientists Discover Protein Partners that Could Heal Heart Muscle | Newsroom - UNC Health and UNC School of Medicine

Cardiac Stem Cells Comments Off on Scientists Discover Protein Partners that Could Heal Heart Muscle | Newsroom – UNC Health and UNC School of Medicine | October 13th, 2022

ReportLinker

Abstract: Whats New for 2022?? Global competitiveness and key competitor percentage market shares. Market presence across multiple geographies - Strong/Active/Niche/Trivial.

New York, Oct. 10, 2022 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Global Induced Pluripotent Stem Cell (iPSC) Industry" - https://www.reportlinker.com/p05798831/?utm_source=GNW

Online interactive peer-to-peer collaborative bespoke updates

Access to our digital archives and MarketGlass Research Platform

Complimentary updates for one yearGlobal Induced Pluripotent Stem Cell ((iPSC) Market to Reach $0 Thousand by 2027- In the changed post COVID-19 business landscape, the global market for Induced Pluripotent Stem Cell ((iPSC) estimated at US$1.4 Billion in the year 2020, is projected to reach a revised size of US$0 Thousand by 2027, growing at a CAGR of -100% over the analysis period 2020-2027. Vascular Cells, one of the segments analyzed in the report, is projected to record a -100% CAGR and reach US$0 Thousand by the end of the analysis period. Taking into account the ongoing post pandemic recovery, growth in the Cardiac Cells segment is readjusted to a revised -100% CAGR for the next 7-year period.- The U.S. Market is Estimated at $629.2 Million, While China is Forecast to Grow at -100% CAGR- The Induced Pluripotent Stem Cell ((iPSC) market in the U.S. is estimated at US$629.2 Million in the year 2020. China, the world`s second largest economy, is forecast to reach a projected market size of US$0 Thousand by the year 2027 trailing a CAGR of -100% over the analysis period 2020 to 2027. Among the other noteworthy geographic markets are Japan and Canada, each forecast to grow at -100% and -100% respectively over the 2020-2027 period. Within Europe, Germany is forecast to grow at approximately -100% CAGR.Neuronal Cells Segment to Record -100% CAGR- In the global Neuronal Cells segment, USA, Canada, Japan, China and Europe will drive the -100% CAGR estimated for this segment. These regional markets accounting for a combined market size of US$188.9 Million in the year 2020 will reach a projected size of US$0 Thousand by the close of the analysis period. China will remain among the fastest growing in this cluster of regional markets.

Select Competitors (Total 51 Featured)Axol Bioscience Ltd.Cynata Therapeutics LimitedEvotec SEFate Therapeutics, Inc.FUJIFILM Cellular Dynamics, Inc.NcardiaPluricell BiotechREPROCELL USA, Inc.Sumitomo Dainippon Pharma Co., Ltd.Takara Bio, Inc.Thermo Fisher Scientific, Inc.ViaCyte, Inc.

Read the full report: https://www.reportlinker.com/p05798831/?utm_source=GNW

I. METHODOLOGY

II. EXECUTIVE SUMMARY

1. MARKET OVERVIEWInfluencer Market InsightsImpact of Covid-19 and a Looming Global RecessionInduced Pluripotent Stem Cells (iPSCs) Market Gains fromIncreasing Use in Research for COVID-19Studies Employing iPSCs in COVID-19 ResearchStem Cells, Application Areas, and the Different Types: A PreludeApplications of Stem CellsTypes of Stem CellsInduced Pluripotent Stem Cell (iPSC): An IntroductionProduction of iPSCsFirst & Second Generation Mouse iPSCsHuman iPSCsKey Properties of iPSCsTranscription Factors Involved in Generation of iPSCsNoteworthy Research & Application Areas for iPSCsInduced Pluripotent Stem Cell ((iPSC) Market: Growth Prospectsand OutlookDrug Development Application to Witness Considerable GrowthTechnical Breakthroughs, Advances & Clinical Trials to SpurGrowth of iPSC MarketNorth America Dominates Global iPSC MarketCompetitionRecent Market ActivitySelect Innovation/AdvancementInduced Pluripotent Stem Cell (iPSC) - Global Key CompetitorsPercentage Market Share in 2022 (E)Competitive Market Presence - Strong/Active/Niche/Trivial forPlayers Worldwide in 2022 (E)

2. FOCUS ON SELECT PLAYERSAxol Bioscience Ltd. (UK)Cynata Therapeutics Limited (Australia)Evotec SE (Germany)Fate Therapeutics, Inc. (USA)FUJIFILM Cellular Dynamics, Inc. (USA)Ncardia (Belgium)Pluricell Biotech (Brazil)REPROCELL USA, Inc. (USA)Sumitomo Dainippon Pharma Co., Ltd. (Japan)Takara Bio, Inc. (Japan)Thermo Fisher Scientific, Inc. (USA)ViaCyte, Inc. (USA)

3. MARKET TRENDS & DRIVERSEffective Research Programs Hold Key in Roll Out of AdvancediPSC TreatmentsInduced Pluripotent Stem Cells: A Giant Leap in the TherapeuticApplicationsResearch Trends in Induced Pluripotent Stem Cell SpaceWorldwide Publication of hESC and hiPSC Research Papers for thePeriod 2008-2010, 2011-2013 and 2014-2016Number of Original Research Papers on hESC and iPSC PublishedWorldwide (2014-2016)Concerns Related to Embryonic Stem Cells Shift the Focus ontoiPSCsRegenerative Medicine: A Promising Application of iPSCsInduced Pluripotent: A Potential Competitor to hESCs?Global Regenerative Medicine Market Size in US$ Billion for2019, 2021, 2023 and 2025Global Stem Cell & Regenerative Medicine Market by Product(in %) for the Year 2019Global Regenerative Medicines Market by Category: Breakdown(in %) for Biomaterials, Stem Cell Therapies and TissueEngineering for 2019Pluripotent Stem Cells Hold Significance for CardiovascularRegenerative MedicineLeading Causes of Mortality Worldwide: Number of Deaths inMillions & % Share of Deaths by Cause for 2017Leading Causes of Mortality for Low-Income and High-IncomeCountriesGrowing Importance of iPSCs in Personalized Drug DiscoveryPersistent Advancements in Genetics Space and Subsequent Growthin Precision Medicine Augur Well for iPSCs MarketGlobal Precision Medicine Market (In US$ Billion) for the Years2018, 2021 & 2024Increasing Prevalence of Chronic Disorders Supports Growth ofiPSCs MarketWorldwide Cancer Incidence: Number of New Cancer CasesDiagnosed for 2012, 2018 & 2040Number of New Cancer Cases Reported (in Thousands) by CancerType: 2018Fatalities by Heart Conditions: Estimated Percentage Breakdownfor Cardiovascular Disease, Ischemic Heart Disease, Stroke,and OthersRising Diabetes Prevalence Presents Opportunity for iPSCsMarket: Number of Adults (20-79) with Diabetes (in Millions)by Region for 2017 and 2045Aging Demographics Add to the Global Burden of ChronicDiseases, Presenting Opportunities for iPSCs MarketExpanding Elderly Population Worldwide: Breakdown of Number ofPeople Aged 65+ Years in Million by Geographic Region for theYears 2019 and 2030Growth in Number of Genomics Projects Propels Market GrowthGenomic Initiatives in Select CountriesNew Gene-Editing Tools Spur Interest and Investments inGenetics, Driving Lucrative Growth Opportunities for iPSCs:Total VC Funding (In US$ Million) in Genetics for the Years2014, 2015, 2016, 2017 and 2018Launch of Numerous iPSCs-Related Clinical Trials Set to BenefitMarket GrowthNumber of Induced Pluripotent Stem Cells based Studies bySelect Condition: As on Oct 31, 2020iPSCs-based Clinical Trial for Heart DiseasesInduced Pluripotent Stem Cells for Stroke Treatment?Off-the-shelf? Stem Cell Treatment for Cancer Enters ClinicalTrialiPSCs for Hematological DisordersMarket Benefits from Growing Funding for iPSCs-Related R&DInitiativesStem Cell Research Funding in the US (in US$ Million) for theYears 2016 through 2021Human iPSC Banks: A Review of Emerging Opportunities and DrawbacksHuman iPSC Banks Worldwide: An OverviewCell Sources and Reprogramming Methods Used by Select iPSC BanksInnovations, Research Studies & Advancements in iPSCsKey iPSC Research Breakthroughs for Regenerative MedicineResearchers Develop Novel Oncogene-Free and Virus-Free iPSCProduction MethodScientists Study Concerns of Genetic Mutations in iPSCsiPSCs Hold Tremendous Potential in Transforming Research EffortsResearchers Highlight Potential Use of iPSCs for DevelopingNovel Cancer VaccinesScientists Use Machine Learning to Improve Reliability of iPSCSelf-OrganizationSTEMCELL Technologies Unveils mTeSR? PlusChallenges and Risks Related to Pluripotent Stem CellsA Glance at Issues Related to Reprogramming of Adult Cells toiPSCsA Note on Legal, Social and Ethical Considerations with iPSCs

4. GLOBAL MARKET PERSPECTIVETable 1: World Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Geographic Region -USA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld Markets - Independent Analysis of Annual Sales in US$Thousand for Years 2020 through 2025 and % CAGR

Table 2: World 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Geographic Region - Percentage Breakdown ofValue Sales for USA, Canada, Japan, China, Europe, Asia-Pacificand Rest of World Markets for Years 2021 & 2025

Table 3: World Recent Past, Current & Future Analysis forVascular Cells by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 4: World 5-Year Perspective for Vascular Cells byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 5: World Recent Past, Current & Future Analysis forCardiac Cells by Geographic Region - USA, Canada, Japan, China,Europe, Asia-Pacific and Rest of World Markets - IndependentAnalysis of Annual Sales in US$ Thousand for Years 2020 through2025 and % CAGR

Table 6: World 5-Year Perspective for Cardiac Cells byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 7: World Recent Past, Current & Future Analysis forNeuronal Cells by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 8: World 5-Year Perspective for Neuronal Cells byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 9: World Recent Past, Current & Future Analysis for LiverCells by Geographic Region - USA, Canada, Japan, China, Europe,Asia-Pacific and Rest of World Markets - Independent Analysisof Annual Sales in US$ Thousand for Years 2020 through 2025 and% CAGR

Table 10: World 5-Year Perspective for Liver Cells byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 11: World Recent Past, Current & Future Analysis forImmune Cells by Geographic Region - USA, Canada, Japan, China,Europe, Asia-Pacific and Rest of World Markets - IndependentAnalysis of Annual Sales in US$ Thousand for Years 2020 through2025 and % CAGR

Table 12: World 5-Year Perspective for Immune Cells byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 13: World Recent Past, Current & Future Analysis forOther Cell Types by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 14: World 5-Year Perspective for Other Cell Types byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 15: World Recent Past, Current & Future Analysis forCellular Reprogramming by Geographic Region - USA, Canada,Japan, China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 16: World 5-Year Perspective for Cellular Reprogrammingby Geographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 17: World Recent Past, Current & Future Analysis for CellCulture by Geographic Region - USA, Canada, Japan, China,Europe, Asia-Pacific and Rest of World Markets - IndependentAnalysis of Annual Sales in US$ Thousand for Years 2020 through2025 and % CAGR

Table 18: World 5-Year Perspective for Cell Culture byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 19: World Recent Past, Current & Future Analysis for CellDifferentiation by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 20: World 5-Year Perspective for Cell Differentiation byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 21: World Recent Past, Current & Future Analysis for CellAnalysis by Geographic Region - USA, Canada, Japan, China,Europe, Asia-Pacific and Rest of World Markets - IndependentAnalysis of Annual Sales in US$ Thousand for Years 2020 through2025 and % CAGR

Table 22: World 5-Year Perspective for Cell Analysis byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 23: World Recent Past, Current & Future Analysis forCellular Engineering by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 24: World 5-Year Perspective for Cellular Engineering byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 25: World Recent Past, Current & Future Analysis forOther Research Methods by Geographic Region - USA, Canada,Japan, China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 26: World 5-Year Perspective for Other Research Methodsby Geographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 27: World Recent Past, Current & Future Analysis for DrugDevelopment & Toxicology Testing by Geographic Region - USA,Canada, Japan, China, Europe, Asia-Pacific and Rest of WorldMarkets - Independent Analysis of Annual Sales in US$ Thousandfor Years 2020 through 2025 and % CAGR

Table 28: World 5-Year Perspective for Drug Development &Toxicology Testing by Geographic Region - Percentage Breakdownof Value Sales for USA, Canada, Japan, China, Europe,Asia-Pacific and Rest of World for Years 2021 & 2025

Table 29: World Recent Past, Current & Future Analysis forAcademic Research by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 30: World 5-Year Perspective for Academic Research byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 31: World Recent Past, Current & Future Analysis forRegenerative Medicine by Geographic Region - USA, Canada,Japan, China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 32: World 5-Year Perspective for Regenerative Medicine byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 33: World Recent Past, Current & Future Analysis forOther Applications by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 34: World 5-Year Perspective for Other Applications byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

III. MARKET ANALYSIS

UNITED STATESInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in the United Statesfor 2022 (E)Table 35: USA Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 36: USA 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Cell Type - Percentage Breakdown of Value Salesfor Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells,Immune Cells and Other Cell Types for the Years 2021 & 2025

Table 37: USA Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 38: USA 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Research Method - Percentage Breakdown of ValueSales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 39: USA Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 40: USA 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

CANADATable 41: Canada Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 42: Canada 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Cell Type - Percentage Breakdown of ValueSales for Vascular Cells, Cardiac Cells, Neuronal Cells, LiverCells, Immune Cells and Other Cell Types for the Years 2021 &2025

Table 43: Canada Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 44: Canada 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Research Method - Percentage Breakdown ofValue Sales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 45: Canada Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 46: Canada 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

JAPANInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in Japan for 2022 (E)Table 47: Japan Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 48: Japan 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Cell Type - Percentage Breakdown of Value Salesfor Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells,Immune Cells and Other Cell Types for the Years 2021 & 2025

Table 49: Japan Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 50: Japan 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Research Method - Percentage Breakdown of ValueSales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 51: Japan Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 52: Japan 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

CHINAInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in China for 2022 (E)Table 53: China Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 54: China 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Cell Type - Percentage Breakdown of Value Salesfor Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells,Immune Cells and Other Cell Types for the Years 2021 & 2025

Table 55: China Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 56: China 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Research Method - Percentage Breakdown of ValueSales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 57: China Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 58: China 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

EUROPEInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in Europe for 2022 (E)Table 59: Europe Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Geographic Region -France, Germany, Italy, UK and Rest of Europe Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 60: Europe 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Geographic Region - Percentage Breakdown ofValue Sales for France, Germany, Italy, UK and Rest of EuropeMarkets for Years 2021 & 2025

Table 61: Europe Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 62: Europe 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Cell Type - Percentage Breakdown of ValueSales for Vascular Cells, Cardiac Cells, Neuronal Cells, LiverCells, Immune Cells and Other Cell Types for the Years 2021 &2025

Table 63: Europe Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 64: Europe 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Research Method - Percentage Breakdown ofValue Sales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 65: Europe Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 66: Europe 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

FRANCEInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in France for 2022 (E)Table 67: France Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 68: France 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Cell Type - Percentage Breakdown of ValueSales for Vascular Cells, Cardiac Cells, Neuronal Cells, LiverCells, Immune Cells and Other Cell Types for the Years 2021 &2025

Table 69: France Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 70: France 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Research Method - Percentage Breakdown ofValue Sales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 71: France Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 72: France 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

GERMANYInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in Germany for 2022 (E)Table 73: Germany Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 74: Germany 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Cell Type - Percentage Breakdown of ValueSales for Vascular Cells, Cardiac Cells, Neuronal Cells, LiverCells, Immune Cells and Other Cell Types for the Years 2021 &2025

Table 75: Germany Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 76: Germany 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Research Method - Percentage Breakdown ofValue Sales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 77: Germany Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 78: Germany 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

ITALYTable 79: Italy Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 80: Italy 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Cell Type - Percentage Breakdown of Value Salesfor Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells,Immune Cells and Other Cell Types for the Years 2021 & 2025

Table 81: Italy Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 82: Italy 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Research Method - Percentage Breakdown of ValueSales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 83: Italy Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 84: Italy 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

UNITED KINGDOMInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in the United Kingdomfor 2022 (E)Table 85: UK Recent Past, Current & Future Analysis for InducedPluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells,Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells andOther Cell Types - Independent Analysis of Annual Sales in US$Thousand for the Years 2020 through 2025 and % CAGR

Table 86: UK 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Cell Type - Percentage Breakdown of Value Salesfor Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells,Immune Cells and Other Cell Types for the Years 2021 & 2025

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Global Induced Pluripotent Stem Cell ((iPSC) Market to Reach $0 Thousand by 2027 - Yahoo Finance

Cardiac Stem Cells Comments Off on Global Induced Pluripotent Stem Cell ((iPSC) Market to Reach $0 Thousand by 2027 – Yahoo Finance | October 13th, 2022

Self-organizing lumps of human brain tissue grown in the laboratory have been successfully transplanted into the nervous systems of newborn rats in a step towards finding new ways to treat neuropsychiatric disorders.

The 3D organoids, developed from stem cells to resemble a simplified model of the human cortex, connected and integrated with the surrounding tissue in each rat's cortex to form a functional part of the rodent's own brain, displaying activity related to sensory perception.

This, according to a team of researchers led by neuroscientist Sergiu Paca of Stanford University, overcomes the limitations of dish-grown organoids, and gives us a new platform for modeling human brain development and disease in a living system.

"Most of the work that my lab has been doing has been motivated by this mission of trying to understand psychiatric disorders at the biological level so that we can actually find effective therapeutics," Paca explained in a press briefing.

"Many of these psychiatric conditions, such as autism and schizophrenia, are likely uniquely human, or at least, they are anchored in unique features of the human brain. And the human brain has certainly not been very accessible, which has precluded the progress we've been making in understanding the biology of these conditions."

In 2008, scientists made a breakthrough: brain cells grown from induced pluripotent stem cells. Mature cells harvested from adult humans were reverse engineered (or induced) to return them to the 'blank' state of stem cells the form cells take before they grow into cells with specializations, such as skin cells or cardiac cells.

These stem cells were then guided to develop into brain cells, which scientists cultivated to form lumps of brain-like tissue called organoids. These models of key areas of brain anatomy, such as the wrinkled outer cortex, could be used to study functions and development of brains up close.

As useful as they are, in vitro cortical organoids have limitations. Because they aren't connected to living systems, they don't complete maturation, depriving researchers of an opportunity to observe how they integrate with other major parts of a brain.

In addition, a brain organoid in a dish can't reveal the behavioral consequences of any defects scientists might identify. Since psychiatric disorders are defined by behavior, this stymies the ability to identify the physiological characteristics of these disorders.

In previous research, scientists have tried to overcome these hurdles by implanting human brain organoids into the brains of adult rats. Because of the developmental mismatch, the transplants didn't take: the developing neurons in the organoid couldn't form a strong connection with the fully developed network of an adult rat brain.

So Paca and his colleagues tried something else: grafting the human brain tissue onto the brains of newborn rats, whose own brains have not yet developed and matured.

Human cortical organoids were cultured in a dish, and then transplanted directly into the somatosensory cortex (the area of the brain responsible for receiving and processing sensory information) of rat pups just a few days old. These rats were then left to grow into adults for another 140 days (rats are fully sexually mature between 6 and 12 weeks).

Then, the scientists studied the rats. They had genetically engineered the organoids to respond to blue light simulation, activating neurons when blue light is shone on them. This stimulation on the human neurons was performed while the rats were being trained to lick a spout to receive water. Later, when the blue light was shone on the organoids, the rats would automatically lick displaying a response not seen in control groups.

This indicated that not only was the organoid functioning as part of the rat brain, it could help drive reward-seeking behavior.

Another group of neurons in the organoid showed activity when the scientist pushed the rats' whiskers evidence that the neurons can respond to sensory stimulation.

Brain cells cultivated from three human patients with a genetic disease called Timothy syndrome were also used for some of the organoids. Timothy syndrome affects the heart, digits and nervous system, and usually results in early death.

After the behavioral tests, the rats were euthanized and their brains extracted and dissected, allowing the researchers to observe the integration of the organoids on a cellular level. They found the organoid neurons grew much larger than any neurons grown in vitro, extending into the rats' brains and forming networks with the native rat neurons.

The neurons in the rats with Timothy syndrome transplants showed less elaborate shapes, and formed different synaptic connections with the surrounding brain tissue compared to control groups. This is a new discovery, and could not have been discovered in a brain organoid in a dish.

Although the platform still has some limitations, the team believes that it has the potential to become a powerful new tool for understanding brain development and disease.

"Overall, this in vivo platform represents a powerful resource to complement in vitro studies of human brain development and disease," the authors write in their paper.

"We anticipate that this platform will allow us to uncover new circuit-level phenotypes in patient-derived cells that have otherwise been elusive and to test novel therapeutic strategies."

The research has been published in Nature.

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Scientists Spliced Human Brain Tissue Into The Brains of Baby Rats - ScienceAlert

Cardiac Stem Cells Comments Off on Scientists Spliced Human Brain Tissue Into The Brains of Baby Rats – ScienceAlert | October 13th, 2022

Tissue source and processing

Paired sections of tissue, including both artery and plaque, were recovered from the atherosclerotic core (AC) and proximally adjacent (PA) region of three patients with asymptomatic type VII calcified plaques who underwent carotid endarterectomy (Fig. S1a, TableS1). Due to the rich cellular composition of carotid artery and plethora of debris in plaque (i.e., lipid, fibrinogen, etc.), dissociation and generation of single-cell suspensions amenable to single-cell RNA sequencing were difficult. After tissue collection, enzymatic digestion, RBC lysis, and filtration were the initial steps required to generate single cells (see Methods and Fig. S1b). However, despite efficient enzymatic dissociation and significant filtering of our sample, we were still challenged by abundant plaque debris, which ultimately resulted in poor single-cell capture rates. In order to overcome this issue without isolating specific cell types through cell-marker antibody labeling, we devised a strategy to label all cells in the sample with a far-red excitation-emission live/dead cell nuclear stain (DRAQ5). All cells in the sample were stained, with debris being left unstained by the dye. Previous studies have used nuclear staining in library preparation and sequencing experiments to discriminate single versus doublet cells during cell sorting without adverse effects for downstream applications such as single-cell and bulk RNA sequencing17,18,19,20. Subsequently, DRAQ5+ cells were manually gated and sorted from the remainder of the debris using FACS. Cells isolated from the entire filtered sample represented <1% of the total particles in the sample (Figs. S2aS2f). Viability of remaining cells was assessed and was always >80% using this technique for cell separation (see Methods). The cells were then processed for single-cell sequencing.

The analytical approach in this manuscript is depicted in Fig.1a. Generation of single cells from three patient-matched AC and PA samples (batched per patient on a single NextSeq flow cell) yielded 51,981 cells total, with an average of ~13,000 AC cells/patient and ~5000PA cells/patient. Cell number disparities are due to the difference in size of the AC vs PA tissue itself. Given the abundance of AC versus PA cells, down-sampling was performed to equalize the contribution of each sample and condition to the unsupervised discovery of cell types and to mitigate bias due to class imbalance. UMAP-based clustering (see Methods) of this down-sampled dataset reveals 15 distinct cell partitions (Fig. S1c, d), representing 17,100 cells total. In order to assign partitions to major cell types we examined genes expressed in >80% of cells per partition and at a mean expression count >2. A dotplot representing three marker genes selected for each partition is presented in (Fig. S1e). A comparison of VSMC marker genes used in our study with those in the literature15 is provided (Fig. S1f). Cell-type labels assigned to these 15 initial partitions based on these marker genes include: T-lymphocytes (2 partitions), macrophages, VSMCs (2 partitions), ECs (2 partitions), B-lymphocytes, natural killer T-cells, B1-lymphocytes, mast cells, lymphoid progenitors, plasmacytoid dendritic cells, and an unidentified partition (TableS2). Following doublet filtering using a marker-gene exclusion method (see Supplemental Methods), removal of partitions with too few cells for differential gene expression analysis (mast cells, lymphoid progenitors, plasmacytoid dendritic cells, and the unidentified partition), and merging of partitions assigned to the same cell-type, we assessed differential gene expression between AC and PA regions across the 6 remaining major cell types: macrophages, ECs, VSMCs, NKT cells, T- and B-lymphocytes (Fig.1bd, Fig. S4, Supplementary Data16). We performed a number of independent partitioning experiments using various algorithmic variations to confirm the reproducibility of these partitions and cell-label assignments (see Supplemental Methods).

a Schematic diagram of analytical steps from tissue dissociation to key driver analysis. b, c UMAP visualization of 6 major cell types following doublet removal via gene exclusion criteria (see Supplemental Methods), separated by anatomic location (b), and by cell type (c). d Dotplot depicting cell-type marker genes, resulting in the identification of macrophages, ECs, VSMCs, NKT cells, T- and B-Lymphocytes. Dot size depicts the fraction of cells expressing a gene. Dot color depicts the degree of expression of each gene. n=3 for PA and AC groups.

GWAS results have highlighted biological processes in the vessel wall as key drivers of coronary artery disease (CAD)21. Our prior work has demonstrated the vascular wall to be involved in the most impactful common genetic risk factor for CAD22. Our results here also demonstrate extensive differential expression in these cell types across anatomic locations compared to the remaining cell types. Therefore, we chose to focus our efforts on dissecting expression alterations in VSMCs and ECs in order to illuminate pathogenic genomic signatures within these cell-types. As above, each cell type is compared across anatomic location (Fig.2a, e), and the top differentially expressed genes are shown (Fig.3b, f), revealing interesting spatial and expression magnitude differences between AC and PA cells.

a, e UMAP visualization of VSMCs (a) and ECs (e), separated by anatomic location. b, f Volcano plots of the top differentially expressed genes in VSMCs (b) and ECs (f). Dotted lines represented q-value 0.5 and <0.5 corresponding to PA and AC cells, respectively. c, d UMAP visualization of the top 4 upregulated genes in AC VSMCs (c), and PA VSMCs (d). Gray-colored cells indicate 0 expression of designated gene, while color bar gradient indicates lowest (black) to highest (yellow) gene expression level. g, h UMAP visualization of the top 4 upregulated genes in AC ECs (g), and PA ECs (h). Color scheme is similar to the above-described parameters. VSMCs=3674 cells; ECs=2764 cells. n=3 for PA and AC groups.

a, b Normalized enrichment score (NES) ranking of all significant PA and AC Hallmarks generated from GSEA analysis of differentially expressed genes for VSMCs (a) and ECs (b) (FDR q-value<0.05). c Fully clustered on/off heatmap visualization of overlap between leading edge EMT hallmark genes generated by GSEA. Heatmaps are downsampled and represent 448 cells from each cell type and anatomic location (1792 total cells). A dotplot corresponding to gene expression levels for each cell type in the heatmap is included. Dot size depicts the fraction of cells expressing a gene. Dot color depicts the degree of expression of each gene. d Volcano plot of differentially expressed genes between the two groups of VSMCs in (c). Dotted lines represented q-value<0.01 and normalized effect >0.5 and <0.5. e, f Gene co-expression networks generated from VSMC Module 13 (d) and EC Module 1 (e) representing the EMT hallmark from GSEA analysis. Genes are separated by anatomic location (red=AC genes, cyan=PA genes), differential expression (darker shade=higher DE, gray=non-significantly DEGs), correlation with other connected genes (green line=positive correlation, orange line=negative correlation) and strength of correlation (connecting line thickness). Significantly DEGs (q<0.05) with high connectivity scores (>0.3) are denoted by a box instead of a circle. n=3 for PA and AC groups.

VSMCs generate three subclusters in the UMAP plot. A large fraction of PA VSMCs form a PA-specific VSMC subcluster. In contrast, AC VSMCs form 2 separate clusters both of which are intermingled with PA VSMCs. This suggests VSMCs occupy three major cell states, including one completely distinct PA subtype, and two that are predominantly AC VSMCs (Fig.2a). The top four upregulated genes in the AC are sparsely expressed and include SPP1, SFRP5, IBSP, and CRTAC1 (Fig.2b, c), while APOD, PLA2G2A, C3, and MFAP5 are upregulated in many PA VSMCs (Fig.2b, d).

The spatial clustering of upregulated genes in AC VSMCs suggests the presence of separate subpopulations of matrix-secreting VSMCs involved with ECM remodeling (Fig.2c). SPP1 (osteopontin) is a secreted glycoprotein involved in bone remodeling23 and has been implicated in atherosclerosis for inhibiting vascular calcification and inflammation in the plaque milieu24. IBSP (bone sialoprotein) is a significant component of bone, cartilage, and other mineralized tissues25. CRTAC1 is a marker to distinguish chondrocytes from osteoblasts and other mesenchymal stem cells26,27. These findings suggest the presence of cartilaginous and osseous matrix-secreting VSMCs in the AC region. SFRP5, an adipokine that is a direct WNT antagonist, reduces the secretion of inflammatory factors28 and is thought to exert favorable effects on the development of atherosclerosis29. The high expression of SFRP5 in the AC suggests a deceleration of these inflammatory processes in the core of the plaque, and an overall shift in the AC to calcification and matrix remodeling.

Conversely, the upregulated genes in PA VSMCs are more ubiquitously expressed by VSMCs in a PA-specific region of the UMAP plot (Fig.2d). C3 is highly differentially expressed in many PA cells (Fig.2d). Complement activation has long been appreciated for its role in atherosclerosis30, with maturation of plaque shown to be dependent, in part, on C3 opsonization for macrophage recruitment and stimulation of antibody responses31. Its predominance in our PA samples suggests complement activation in atherosclerosis is anatomically driven by VSMCs located adjacent to areas of maximal plaque build-up. PLA2G2A (phospholipase A2 group IIA), also selectively expressed by this group of cells, is pro-atherogenic, modulates LDL oxidation and cellular oxidative stress, and promotes inflammatory cytokine secretion32, further facilitating the inflammatory properties of this group of VSMCs. Full differential expression results for VSMCs are provided (Supplementary Data5).

Overall, we identify increased calcification and ECM remodeling by VSMCs in the AC versus pro-inflammatory signaling by VSMCs in the PA. These differences in biological processes are strongly supported further in the systems analyses below.

In contrast to VSMCs, for ECs we observe a more complete separation of cells into two distinct subgroups (Fig.2e). PA ECs significantly outnumber the AC ECs (2316 vs 448 cells, respectively), possibly due to intimal erosion and loss of endothelial cell layer integrity during advanced disease5,33,34,35 resulting in fewer captured ECs in the AC. Cellular transdifferentiation may also cause a subpopulation of ECs to lose common EC marker expression, resulting in lower numbers of ECs identified in AC compared to the PA counterpart. Histologic assessment of AC plaque collected from our patients supports the assertion of endothelial layer attenuation as the principal reason for lower AC EC capture (Fig. S3b, c). In contrast to VSMCs, there is a skew toward higher magnitude expression changes in AC ECs vs PA ECs. The top four upregulated genes are ITLN1, DKK2, F5, and FN1 in the AC and IL6, MLPH, HLA-DQA1, and ACKR1 in PA ECs (Fig.2g, h).

The upregulated genes in AC ECs again suggest a synthetic profile. ITLN (omentin) is an adipokine enhancing insulin-sensitivity in adipocytes36. Interestingly, circulating plasma omentin levels were shown to negatively correlate with carotid intima-media thickness37, inhibit TNF-induced vascular inflammation in human ECs38, and promote revascularization39, suggesting an anti-inflammatory and intimal repair role in AC ECs. DKK2 further indicates intimal repair as it stimulates angiogenesis in ECs40. The significant upregulation of FN1 (fibronectin) in this group further suggests active ECM remodeling and may serve as a marker for mesenchymal cells and EMT-related processes41.

Similarly to PA VSMCs, the upregulated genes in PA ECs suggest an overall inflammatory profile. Central players in inflammation and antigen presentation are upregulated specifically in PA ECs (Fig.2h). IL6, a key inflammatory cytokine associated with plaque42, is the most upregulated gene. Furthermore, ACKR1, highly upregulated in many PA ECs, binds and internalizes numerous chemokines and facilitates their presentation on the cell surface in order to boost leukocyte recruitment and augment inflammation43. Antigen presentation on ECs via HLA-DQA1 (MHC class II molecule) may support activation and exhaustion of CD4+ T-cells44,45 as previously described. Full differential expression results for ECs are provided (Supplementary Data6).

Overall, we identify two main EC subtypes: synthetic ECs in the AC that appear to participate in intimal repair, revascularization, and ECM modulation, and inflammatory ECs in the PA region that likely facilitate inflammation via antigen/chemokine presentation and recruitment of immune cells, including CD4+ T-cells. These differences in biological processes are strongly supported further in the systems analyses below.

In order to explore the anatomic differences for these cell types further, gene set enrichment analysis (GSEA) was used to asses hallmark processes most significantly altered in VSMCs and ECs (Fig.3a, b). Epithelial to mesenchymal transition (EMT), oxidative phosphorylation, and myogenesis gene upregulation were strongly enriched in both AC VSMCs and ECs, collectively suggesting an increase in cellular metabolic activity and proliferation. In contrast, a distinctly inflammatory profile was seen in PA VSMCs and ECs, with IFN gamma/alpha responses and TNFa signaling via NFkB dominating the enriched processes in these groups of cells. Because EMT and TNFa signaling were both shared and strongly enriched processes in the two cell types, the gene signatures associated with these hallmarks were further scrutinized through generation of heatmaps consisting of leading-edge differentially expressed genes from each hallmark process (EMTFig.3c, TNFa signaling via NFkBFig. S5a).

While overlapping at the hallmark level, separation of cells by cell type as well as anatomic location in the EMT hallmark heatmap suggests the overlapping processes are mediated by distinct gene sets in each cell type. Moreover, analysis of EMT hallmark genes further supports the presence of 2 cellular subtypes of AC VSMCs as they appear to cluster into two distinct groups of cells with dichotomous expression of contractile (MYL9, TPM2, TAGLN, FLNA) versus synthetic/EMT (POSTN, LUM, FBLN2, DCN, PCOLCE2, MGP, COL3A1) gene signatures (Fig.3c, d). These results indicate a group of VSMCs in the AC may perform the contractile functions of the blood vessel wall, while the other group of VSMCs may be involved with CTD and ECM remodeling. Furthermore, cells with an ACTA2+Thy1 gene signature in Fig.3c may be, in part, plaque-stabilizing myofibroblasts (orange line), indicating that these contractile cells may also have a large role in ECM remodeling.

In contrast to distinct subclustering of cells by EMT-related genes, there appears to be a common gradient of genes involved in inflammation and response to inflammation expressed throughout the atherosclerotic tissue, with higher levels of TNF-related inflammatory genes expressed in PA VSMCs and ECs compared to AC cells, indicating a predominance of inflammatory processes occurring in the PA region overall (Fig. S5a). Collectively these genes (EIF1, FOS, JUN, JUNB, ZFP36, PNRC1, KLF2, IER2, CEBPD, NFKBIA, GADD45B, EGR1, PPP1R15A, and SOCS3), in addition to IL6 expression in PA ECs, appear to coordinate the inflammatory response pathways in plaque and its adjacent structures. All cell types analyzed thus far are coordinated along this gradient of inflammation.

To further dissect VSMC and EC anatomical gene expression differences in order to identify candidate key genes driving the significant hallmark processes, we reconstructed gene co-expression networks using a partial correlation-based approach (see Methods), defined modules by clustering, and overlaid differential expression analysis results on these modules to identify those enriched in genes differentially expressed between AC and PA tissues.

Using this strategy, 31 and 39 distinct gene network modules were generated in our VSMC and EC datasets, respectively (see Supplemental Methods, Supplementary Data7, 8). Of these, 8 modules in VSMCs, and 5 modules in ECs were enriched with differentially expressed genes (p-value<0.05, Fishers exact test, see Methods). Furthermore, differentially expressed EMT-related hallmark genes overlapped significantly and specifically with a single VSMC and EC module. Differentially expressed TNFa signaling via NFkB-related hallmark genes also overlapped significantly with one VSMCs and EC module (p-value<0.05, Fishers exact test). No other hallmark processes overlapped with generated network modules.

The EMT gene signature generated from GSEA analysis of network modules and the robust upregulation of genes found in matrix-secreting cells in this cohort suggests the possibility of CTD occurring and/or completing in the atherosclerotic core. Therefore, in order to further characterize genes which may stimulate CTD in AC VSMCs and ECs we examined gene co-expression networks in conjunction with differential expression data from the modules enriched with EMT hallmark genes. In VSMCs we identified 9 genes (SPP1, IBSP, POSTN, MMP11, COL15A1, FN1, COL4A1, SMOC1, TIMP1) whose expression was significantly upregulated in AC cells and with strong network connectivity (see Methods). Among these genes we identify POSTN, SPP1, and IBSP as possible key gene drivers of CTD processes in AC VSMCs due to their strong central connectivity and high degree of differential expression in the network module (Fig.3e). POSTN (periostin) is expressed by osteoblasts and other connective tissue cell types involved with ECM maturation46 and stabilization during EMT in non-cardiac lineages47,48. POSTN, SPP1, and IBSP are highly interconnected in our network and likely serve as drivers of CTD by modulating other correlated genes such as TIMP1, VCAN, TPST2, SMOC1, MMP11, FN1, and COL4A1 (Fig.3e), all genes which are involved with cellular differentiation49 and extracellular matrix remodeling50,51.

In our EC network we identified 18 genes (ITLN1, FN1, OMD, S100A4, SCX, PRELP, GDF7, TMP2, SERPINE2, SLPI, HEY2, IGFBP3, FOXC2, RARRES2, PTGDS, TAGLN, LINC01235, and COL6A2) whose expression was significantly upregulated in AC cells and with strong network connectivity. Among these genes, we identify ITLN1, S100A4, and SCX as possible gene drivers of CTD in ECs associated with the AC (Fig.3f). ITLN1 (omentin) is highly upregulated in ECs associated with the atherosclerotic core, and network data indicate it is strongly correlated with genes involved with cellular proliferation and ECM modulation. ITLN is also strongly correlated to OGN (osteoglycin) which induces ectopic bone formation52, indicating that ITLN1 may modulate ECs with osteoblast-like features in the atherosclerotic core. SCX (scleraxin), a transcription factor that plays a critical role in mesoderm formation, and the development of chondrocyte lineages53, as well as regulating gene expression involved with ECM synthesis and breakdown in tenocytes54, is co-expressed with IL11RA, an interleukin receptor implicated in chondrogenesis55, as well as with a variety of genes involved with cellular development and modulation of ECM structures. Thus, SCX may modulate chondrocyte-like ECs in the AC. S100A4 is a calcium-binding protein that is highly expressed in smooth muscle cells of human coronary arteries during intimal thickening56, and silencing this gene in endothelial cells prevents endothelial tube formation and tumor angiogenesis in mice57. Co-expression with HEY2, a transcription factor involved with NOTCH signaling and critical for vascular development58, may indicate an important role in repair via re-endothelialization of plaque-denuded artery.

Next, genes critical to stimulating TNFa signaling via NFkB in PA VSMCs and ECs were evaluated. In the VSMC module we identified 14 genes (APOLD1, MT1A, ZFP36, EGR1, JUNB, FOSB, JUN, FOS, RERGL, MT1M, DNAJB1, CCNH, HSPA1B, and HSPA1A) whose expression was significantly upregulated in PA cells and with strong network connectivity. Among these genes we identify immediate-early (IE) genes ZFP36, EGR1, JUNB, FOSB, and FOS as critical response genes in this hallmark process. Importantly, the paired-sample study design in which AC and PA samples from the same patient are processed identically at the same time ensures that these IE genes preferentially upregulated in the PA region are critical for the inflammatory response and not an artifact of tissue processing stressors.

In the EC module we identified two genes (IER2 and FOS) whose expression was significantly increased in PA EC cells (Fig. S5e), and are highly correlated with other critical transcription factors in our network, including FOSB, JUNB, EGR1, and ZFP36, further supporting this group of genes importance in the TNFa signaling hallmark (Fig. S5d).

Finally, in order to identify and characterize refined subpopulations from each anatomic region, we selected the 7 VSMC and 5 EC differentially expressed modules described above and biclustered cells and genes (Fig.4a, d). The likely biological functions of these subpopulations were then inferred based on the genes differentially expressed and subsequent gene ontology enrichment analysis across these subpopulations. A continuous gene expression model, based on the fraction of AC cells per subpopulation, and subsequent gene ontology enrichment analysis was used to evaluate these cell subtype differences (Fig.4b, c, e, f).

a, d Biclustered heatmap visualization of all significant genes (q<0.05) from VSMC (a) and EC (d) modules enriched with differentially expressed genes. a 1224 VSMCs from each anatomic location (2448 cells total). Large color bar denotes PA (cyan) and AC (orange) VSMCs. Small color bar above denotes distinct cell subpopulations (blue, forest green, lime green, brown, purple, magenta, red). d 448 ECs from each anatomic location (896 cells total) in. Large color bar denotes PA (blue) and AC (red) ECs. Small color bar above denotes distinct cell subpopulations (cyan, green, magenta). A dotplot corresponding to gene expression levels for each cell subpopulation on the heatmap is included. Colored dots next to specific genes correspond to critical genes related to the designated cell subpopulation. Continuous gene expression based gene ontology enrichment analysis of biological function performed based on the fraction of AC cells per subpopulation of VSMCs (b, c) and ECs (e, f). n=3 for PA and AC groups.

We identified four cell subpopulations of VSMCs with some overlapping features in our analysis (Fig.4a). The four subpopulations appear to form a continuum of cell states, starting with a population that consists exclusively of PA VSMCs (Fig.4a, green bar), characterized by genes involved in recruitment of inflammatory mediators, with early signs of CTD. Specifically, C3 (opsonization and macrophage recruitment; normalized effect=6.5, q=1.74e07) is highly differentially expressed in this subpopulation and likely augments PA inflammation and macrophage recruitment. This group of VSMCs also shows evidence of early migratory and CTD-like qualities given the expression of FBN1, SEMA3C, HTRA3, and C1QTNF3, (normalized effect=2.77, 3.65, 4.0, 3.58, respectively; q=6.93e41, 1.25e20, 2.53e05, 0.00012, respectively) genes that are both highly differentially expressed in this cohort and with high signal strength in our networks (Fig.4a, Supplementary Data7). FBN1 (ECM component) is strongly correlated with TGFBR3, SEMA3C, and CD248 (modulators of EMT-like processes)59,60,61. Interestingly, this group of cells co-expresses IGSF10, a marker of early osteochondroprogenitor cells62, TMEM119 (bone formation and mineralization; promotes differentiation of myeloblasts into osteoblasts)63,64, and WNT11 (bone formation)65 (Supplementary Data7).

On the other end of this continuum, we identify a subpopulation of ~70% AC cells (Fig.4a, red bar) that have elevated expression of POSTN (osteoblasts; normalized effect=2.206, q=3.60e16), CRTAC1 (chrondrocytes; normalized effect=3.22, q=3.91e26), TNFRSF11B (bone remodeling; normalized effect=0.98, q=7.31e06)66, ENG (VSMC migration; normalized effect=0.87, q=1.41e13)67, COL4A2, and COL4A1 (cell proliferation, association with CAD; normalized effect=0.98, 1.03 and q=3.17e15, 5.68e11, respectively)68,69. Collectively, the differential gene expression data and the underlying biology behind our gene co-expression networks support this group of cells as likely representing synthetic osteoblast- and chondrocyte-like VSMCs which facilitate calcification and cartilaginous matrix-secretion and reside largely in the AC.

Furthermore, gene ontology enrichment analysis provides a clear progression from muscle system processes, extracellular structure reorganization, and catabolic processes enriched in the PA to processes involved with CTD such as ossification, fat cell differentiation, and regulation of cell motility, adhesion, and cellular transdifferentiation enriched in the AC (Fig.4b, c). The shift in cell states supports a continuum of cell state changes leading to increased CTD in the atherosclerotic core.

Overall, we observe three EC subpopulations. Like VSMCs, these cells display transitory properties as they move through a continuum of cell states (Fig.4d). First, there is a group comprised near exclusively of inflammatory PA ECs that is involved in recruitment of inflammatory mediators (Fig.4d, magenta bar). This group has a greater number of cells expressing immune genes such as the cluster of HLA genes, as well as CD74 (normalized effect=1.63, q=2.07e112), a gene which forms part of the invariant chain of the MHC II complex and is a receptor for the cytokine macrophage migration inhibitory factor (MIF)70. The upregulation of MHC class II complex in this subset of PA ECs complements our previous finding of CD4+T-cell recruitment to this subpopulation of PA ECs, leading to over-activation and exhaustion via antigen-persistence.

The next group of cells is intermediate in its composition of AC (67.5%) and PA (~32.5%) ECs with a mixed gene expression profile with characteristics similar to each of the other two groups of cells (Fig.4d, green bar), likely representing dysfunctional ECs that are in transition from the inflamed subtype to the CTD subtype described below.

The final group of cells is largely comprised of ECs from the AC (96.8%) (Fig.4d, cyan bar) and is largely devoid of endothelial-marker gene EMCN71 (normalized effect=0.86, q=1.17e09). Critical EMT genes identified earlier (ITLN1, SCX, and S100A4) are predominantly expressed in this large cluster of AC ECs alongside highly correlated genes OMD, OGN, and CRTAC1, again indicating that this population of ECs likely represents the main group of transdifferentiated ECs.

Gene ontology enrichment analysis further supports this shift in EC cell state from cells primarily involved with immune response (antigen processing and presentation, adaptive immune response, etc.) to cell states predominantly involved with proliferation, migration, vascular development, and angiogenesis (Fig.4e, f).

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Synthetic Stem Cells Market

Synthetic stem cells are very fragile and need careful storage, typing, and characterization before use. Synthetic stem cells operate in a very similar way to that deactivated vaccines. The membranes of the synthetic stem cells let them bypass the immune response. Nevertheless, synthetic stem cells can't amplify themselves. Therefore, we benefit from stem cell therapy without risks. The synthetic stem cells are more durable than human stem cells and can withstand severe freezing and thawing. Additionally, these cells are not derived from the patient's individual cells. Synthetic stem cells offer better therapeutic benefits as compared to natural stem cells. Furthermore, these cells have improved preservation stability and the technology is also generalized to other types of stem cells.

The increasing incidents and significant prevalence of several cardiovascular ailments around the world are accentuating the research in varied synthetic kinds of cardiac stem cells. The evolving focus on synthetic stem cell engineering has augmented the growth of the global synthetic stem cell market.

The better stability during preservation and a generalized technology for various types of stem cells are benefits that impart a large momentum to the growth of the synthetic stem cells market. However, the regulatory landscape for the development and approval of synthetic stem cells is very stringent, which poses a genuine challenge to companies hoping for rapid commercialization of the synthetic stem cells market.

The global synthetic stem cells market is divided into applications for neurological disorders, cardiovascular disease, and others (cancer, musculoskeletal disorders, gastrointestinal, and diabetes).

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By region, North America is expected to lead the global synthetic stem cells market over the forecast time period due to the presence of a leading stakeholder-North Carolina State University in the region. The Asia Pacific will experience rapid changes in the compound annual growth rate of the synthetic stem cells market and is anticipated to be one of the major shareholders globally due to the extensive research and development activities witnessed in Zhengzhou University situated in China.

With widespread research and development work being conducted in Europe, the region is expected to trail the Asia Pacific and North America. Latin America and the Middle East and Africa are expected to develop considerably in the future due to the emerging research and development works in this field.

Some key players in the global synthetic stem cells market are North Carolina State University and Zhengzhou University.

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Neurological DisordersCardiovascular DiseaseOthers (Cancer, Musculoskeletal Disorders, Gastrointestinal, and Diabetes)

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Global Synthetic Stem Cells Market Is Expected To Reach Around USD 42 Million By 2025 - openPR

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October 12, 2022 7:15 am ET

Companies on track to report data from the ongoing Phase 2 trial of mRNA-4157/V940 in combination with KEYTRUDA as adjuvant therapy in high-risk melanoma in 4Q 2022

CAMBRIDGE, M.A. and RAHWAY, N.J., October 12, 2022 Moderna, Inc. (Nasdaq: MRNA), a biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines, and Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced that Merck has exercised its option to jointly develop and commercialize personalized cancer vaccine (PCV) mRNA-4157/V940 pursuant to the terms of its existing Collaboration and License Agreement. mRNA-4157/V940 is currently being evaluated in combination with KEYTRUDA, Mercks anti-PD-1 therapy, as adjuvant treatment for patients with high-risk melanoma in a Phase 2 clinical trial being conducted by Moderna.

We have been collaborating with Merck on PCVs since 2016, and together we have made significant progress in advancing mRNA-4157 as an investigational personalized cancer treatment used in combination with KEYTRUDA, said Stephen Hoge, M.D., President of Moderna. With data expected this quarter on PCV, we continue to be excited about the future and the impact mRNA can have as a new treatment paradigm in the management of cancer. Continuing our strategic alliance with Merck is an important milestone as we continue to grow our mRNA platform with promising clinical programs in multiple therapeutic areas.

Under the agreement, originally established in 2016 and amended in 2018, Merck will pay Moderna $250 million to exercise its option for personalized cancer vaccines including mRNA-4157/V940 and will collaborate on development and commercialization. The payment will be expensed by Merck in the third quarter of 2022 and included in its non-GAAP results. Merck and Moderna will share costs and any profits equally under this worldwide collaboration.

This long-term collaboration combining Mercks expertise in immuno-oncology with Modernas pioneering mRNA technology has yielded a novel tailored vaccine approach, said Dr. Eliav Barr, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. We look forward to working with our colleagues at Moderna to advance mRNA-4157/V940 in combination with KEYTRUDA as it aligns with our strategy to impact early-stage disease.

About mRNA-4157/V940

Personalized cancer vaccines are designed to prime the immune system so that a patient can generate a tailored antitumor response to their tumor mutation signature to treat their cancer. mRNA-4157/V940 is designed to stimulate an immune response by generating T cell responses based on the mutational signature of a patients tumor.

About KEYNOTE-942 (NCT03897881)

KEYNOTE-942 is an ongoing randomized, open-label Phase 2 trial that enrolled 157 patients with high-risk melanoma. Following complete surgical resection, patients were randomized to mRNA-4157/V940 (9 doses every three weeks) and KEYTRUDA (200 mg every three weeks) versus KEYTRUDA alone for approximately one year until disease recurrence or unacceptable toxicity. KEYTRUDA was selected as the comparator in the trial because it is considered a standard of care for high-risk melanoma patients. The primary endpoint is recurrence-free survival, and secondary endpoints include distant metastasis-free survival and overall survival. The Phase 2 trial is fully enrolled and primary data are expected in the fourth quarter of 2022.

About KEYTRUDA (pembrolizumab) Injection 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patients likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB, IIC, or III melanoma following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):

Non-muscle Invasive Bladder Cancer

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test.

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval of this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Cancer

KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

KEYTRUDA, in combination with lenvatinib, is indicated for the first-line treatment of adult patients with advanced RCC.

KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

Endometrial Carcinoma

KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis;Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy;Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss;Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis;Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica;Endocrine: Hypoparathyroidism;Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

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Merck and Moderna Announce Exercise of Option by Merck for Joint Development and Commercialization of Investigational Personalized Cancer Vaccine -...

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Introduction

Within the spinal column lies the spinal cord, a vital aspect of the central nervous system (CNS). The three primary roles of the spinal cord are to send motor commands from the brain to the body, send sensory information from the body to the brain, and coordinate reflexes. The spinal cordis organized segmentally, with thirty-one pairs of spinal nerves emanating from it. A spinal cord injury disrupts this conduit between the body and brain and canlead to deficits in sensation, movement, and autonomic regulation, as well as death.

The spinal cord is composed of gray and white matter, appearing in a cross-section as H-shaped gray matter surrounded by white matter. The gray matter consists of the cell bodies of motor and sensory neurons, interneurons,and neuropils (neuroglia cells and mostly unmyelinated axons). In contrast, the white matter is composed of interconnecting fiber tracts, which are primarily myelinated sensory and motor axons. The supports of the gray matters H make up the right dorsal, right ventral, left dorsal, and left ventral horns. Running longitudinally through the center of the spinal cord is the central canal, which is continuous with the brains ventricles and filled with cerebrospinal fluid (CSF).

The white matteris organized into tracts. Ascending tracts carry information from the sensory receptors to higher levels of the CNS, while descending tracts carry information from theCNS to the periphery. The major tracts and their most defining features are as follows:[1]

Ascending Tracts

Dorsal column: contains the gracile fasciculus and cuneate fasciculus, which togetherform the dorsal funiculus. The dorsal column is responsible for pressure and vibration sensation, two-point discrimination, movement sense, and conscious proprioception. The dorsal column decussates at the superior portion of the medulla oblongata and forms the medial lemniscus.

Lateral spinothalamic: carries pain and temperature information. The lateral spinothalamic tract decussates at the anterior commissure, two segments above the entry to the spinal cord.

Descending Tracts

Lateral and anterior corticospinal: involved in conscious control of the skeletal muscle. The majority of lateral corticospinal tract fibers decussate at the inferior portion of the medulla oblongata, while anterior corticospinal descends ipsilaterally in the spinal cord and decussates at the segmental level. The lateral corticospinal tract, also called the pyramidal tract, innervates primarily contralateralmuscles of the limbs, while the anterior corticospinal tract innervates proximal muscles of the trunk.

Vestibulospinal: carries information from the inner ear to control head positioning and is involved in modifying muscle tone to maintain posture and balance. The vestibulospinal tract does not decussate.

Rubrospinal: involved in the movement of the flexor and extensor muscles.The rubrospinal tract originates from the red nuclei in the midbrain and decussates at the start of its pathway.

There is a laminar distribution of neurons in the gray matter, characterized by density and topography:

Lamina II is composed mainly of islet cells with rostrocaudal axes, which contain GABA and are thought to be inhibitory, and stalked cells with dorsoventral dendritic trees.

Lamina V and VI are composed of medium-sized multipolar neurons that can be fusiform or triangular. These neurons communicate with the reticular formation of the brainstem.

Lamina VII is composed of homogenous medium-sized multipolar neurons and contains, in individual segments, well-defined nuclei, including the intermediolateral nucleus (T1-L1), which has autonomic functions, and the dorsal nucleus of Clarke (T1-L2), which make up the dorsal spinocerebellar tract.

Lamina VIII consists of neurons with dorsoventrally polarized dendritic trees.

Lamina IX has the cell bodies of motor neurons, with dendrites extending dorsally into laminas as far as VI. Lamina IX also has Renshaw cells, inhibitory interneurons, placed at the medial border of motor nuclei.

Neurulation begins in the trilaminar embryo when part of the mesoderm differentiates into the notochord. The formation of the notochord signals the overlying ectoderm to form the neural plate, the first structure that will become the nervous system. The neural plate folds in on itself, creating the neural tube, initially open at both ends and ultimately closed. From the neural tube comes the primitive brain and spinal cord.[9]The development of the nervous system begins seventeen days after gestation, and in the fifth week, myotomes start to form, allowing the development of rudimentary reflex circuitries. Myelination of the motor tracts begins in the first few months of life and continues into adolescence.

An interesting note is that reciprocal excitation changes to inhibition between nine and twelve months of age. Before that age, supraspinal descending fibers activate interneurons, resulting in extension or flexion. During this period of development, glycine and GABA are excitatory.[10]

The spinal cord is the conduit between the brain and the rest of the body. It sends motor commands from the motor cortex to the muscles of the body and sensory information from the afferent fibers to the sensory cortex. Additionally, the spinal cord can act without signals from the brain in certain instances. The spinal cord independently coordinates reflexes using reflex arcs.Reflex arcs allow the body to respond to sensory information without waiting for input from the brain. The reflex arc starts with a signal from a sensory receptor, which is carried to the spinal cord via a sensory nerve fiber, synapsed on an interneuron, carried over to the motor neuron, which stimulates an effector muscle or organ.[11]The spinal cord also has central pattern generators, which are interneurons that form the neural circuits, which control rhythmic movements. Although the existence of central pattern generators in humans is controversial, the lumbar spinal cord produces rhythmic muscle activation without volitional motor control or step-specific sensory feedback, suggesting their role in human movement.[12]

Three connective tissue layers,termed meninges, conceal the spinal cord. Directly lining the spinal cord is the pia mater, which also thickens to form the denticulate ligament, anchoring the spinal cord in the middle of the vertebral canal. The next layer of meninges is the arachnoid mater.Between the pia mater and arachnoid mater is the subarachnoid space, which contains CSF. On top of the arachnoid mater is the last layer of meninges, the dura mater, then the epidural space separating the meninges from the vertebral column.[13]

The spinal cord extends from the medulla oblongata of the brain stem at the level of the foramen magnum. In an adult human, the spinal cord gives rise to thirty-one pairs of spinal nerves, each of which originates from the adjacent spinal cord segment:

Spinal nerves emerge from the spinal cord as rootlets, whichjoin together to form two nerve roots.The anterior nerve roots contain motor fibers extending from the anterior horn to peripheral target organs. The motor neurons are multipolar, with at least two dendrites, a single axon, and one or more collateral branches. They control skeletal muscles and the autonomic nervous system. The posterior nerve roots contain sensory fibers and dorsal root ganglia. They contain sensory fibers transmitting sensory information from the periphery towards the CNS. The sensory neurons located at the dorsal root ganglia are pseudounipolar. The anterior and posterior nerve roots converge into spinal nerves, which split into dorsal and ventral rami.A dermatome is a skin area innervated by a single spinal nerve root (or spinal cord segment).

There are five spinal plexuses, which include sensory and motor nerves from the anterior rami:

Cervical plexus (C1-C5): the deep branches innervate neck muscles, and the superficial branches innervate the skin on the neck, head, and chest. The cranial plexus also has an autonomic function, including controlling the diaphragm and interactions with the vagus nerve.

Brachial (C5-T1): controls movement and sensation of the upper extremity.

Lumbar (L1-L4): controls movement and sensation of the abdominal wall, thigh, and external genitals.

Sacral (L4, L5, S1-S4): controls movement and sensation of the foot, leg, and thigh.

Coccygeal (S4, S5, Co): innervates the skin around the tailbone.

In adults, the spinal cord tapers to an end, termed the conus medullaris, at the second lumbar vertebra level. Past the conus medullaris, a bundle of spinal roots extends termed the cauda equina. The cauda equina and the subarachnoid space continue until S2 and is the target location for a lumbar puncture (spinal tap).

Electrophysiological Testing

Evoked potentials (EPs) measure electrical signals going to the brain and can determine whether there is motor or somatosensory impairment. The signal is detected by electroencephalography (EEG) or electromyography (EMG). Evoked potentialsmay be used to assess spinal cord damage in the setting of spinal cord injury and tumors, and measure functional impairment and predict disease progression in multiple sclerosis.[15]Somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs)are frequentlyused intra-operatively for monitoring and can be used post-operatively as surrogate endpoints to check muscle strength and sensory status.[16]

Nerve conduction studies determine whether there has been an injury to a spinal nerve root, peripheral nerve, neuromuscular junction, muscle, cranial nerve, or spinal nerve. They can also be used to pinpoint spinal cord lesions.Nerve conduction studies work by stimulating nerves close to the skin or using a needle placed near a nerve or nerve root. Neurologists often use them with needle electromyograms.[17]

Lumbar Puncture

A lumbar puncture, or spinal tap, samples the CSF from the subarachnoid space. The needle to obtain the sample should be inserted between lumbar spinal canal levels L3 and L4 to avoid contact with the spinal cord.[18]TheCSF is then sent to a laboratory to establish whether any insult can be determined.For instance, a lumbar puncture can confirm or exclude bacterial meningitis, which will produce a cloudy fluid suggestive of a high leukocyte count. It is also important to know when not to use a lumbar puncture. Contraindications to lumbar puncture include signs of cerebral herniation, focal neurological signs, uncorrected coagulopathies, or cardiorespiratory compromise.[19]

Deep Tendon Testing

One aspect of theneurological exam is a test of the deep tendon reflexes, which are involuntary motor responses to various stimuli that function via reflex arcs within the spinal cord. They can be used to test the function of the motor and sensory nerves at specific spinal cord levels.Reflex grading is on a scale of 0 (absent reflex) to 5+ (sustained clonus).[20]Some commonly tested reflexes are as follows:

Additionally, the Babinski reflex, or the extensor plantar reflex, can be seen in newborns but is an abnormal response aftersix to twelve months of age. If the Babinski reflex is seen after 12 months of age, it may indicate an abnormality in the corticospinal system.[21]

Spinal Cord Injury

Primary spinal cord injury occurs due to local deformation of the spine, such as direct compression. Secondary spinal cord injury occurs following primary damage and involves cascades of biochemical and cellular processes, including electrolyte disturbances, free radical damage, edema, ischemia, and inflammation.[22]Secondary spinal cord injury has several phases: acute, subacute, and chronic. During the acute phase (up to 48 hours after the primary injury), hemorrhage and ischemia lead to ion balance disruption, excitotoxicity, and inflammation. During the subacute phase (up to two weeks following primary injury), there is a phagocytic response and a reactive proliferation of astrocytes, which leads to a glial scar in the chronic phase. The thinking is that scarification is the critical component to permanent disability because it prevents axonal regeneration; axons otherwise could regenerate, but their growth is blocked. However, that notion has been subject to challenge, and there are suggestions that astrocyte scar formation could aid in regeneration.[23]In the chronic phase (over six months after the primary injury), the scarification process is complete.[24]

Developmental

Open neural tube defects occur when there is a failure of the neural tube to close. If it fails to close at the cranial end, the fetusmay develop anencephaly. If the failure is at the caudal end, the fetusmay have myelomeningocele or open spina bifida. Craniorachischisis can also occur if the entire neural tube remains open. Closed neural tube defects are spinal cord development problems that are skin-covered, such as occult spina bifida.Folic acid supplements lower the risk of neural tube defects, although severe folate deficiency in mouse models does not lead to neural tube defects unless there is already a genetic predisposition. Suggestions are that folate can overcome a genetic predispositionfor adverse effects, potentially leading to neural tube defects.[25]

A spinal cord injury can be classified as complete or incomplete. A complete injury, based on the International Standard Neurological Classification of Spinal Cord Injury (ISNCSCI) examination, developed by the American Spinal Cord Injury Association (ASIA), implies that there is no sensation at the inferior segments of the spinal cord (S4-S5); no deep anal pressure (DAP) or voluntary anal contraction (VAC) is present. If no perianal sensation is present and DAP and VAC are absent, the present function below the level of injury is a zone of partial preservation.[26]

An injury in the cervical region often results in quadriplegia if both sides of the spinal cord are affected and hemiplegia if only one side is affected. Nerves from C3, C4, and C5 stimulate the phrenic nerve, which controls the diaphragm, so injury to C4 and above may result in a permanent need for a ventilator. An injury to the thoracic region often limits the function of nerves related to the lower torso and lower extremities. Usually, it does not affect the upper torso and upper extremities, except in rare cases such as subacute posttraumatic ascending myelopathy (SPAM).[27]Injury to thespinal cord often causes loss of bowel and bladder control, loss of sexual function, and blood pressure dysregulation, as the spinal cordrelays autonomic and somatic information.

Syndromes

Several syndromes correlate with spinal cord injury. Central cord syndrome usually occurs in individuals who suffer a hyperextension injury, and it often leads to incomplete injury with weakness predominantly affecting the upper limbs. The reason for this phenomenon is the organization of the fibers in the spinal cord: the fibers running to the lower extremities are longer than those running to the upper extremities; the longer fibers are located more laterally in the spinal cord (L-L rule). As the central portion of the spinal cord is injured, there is a sparing of the fibers running to the lower extremities. Brown-Sequard syndrome is due to a spinal cord hemisection,leading to a complete loss of sensation at the level of the lesion, as well as deficits below the lesion loss of proprioception, vibration, and motor control, ipsilaterally, and a loss of pain and temperature sensation, contralaterally. Anterior cord syndrome is due to a compromised blood supply to the anterior two-thirds of the spinal cord, damaging the corticospinal and spinothalamic tracts.This syndrome is associated with several deficits at and below the lesion, including motor loss and a loss of pain and temperature sensation. However, light touch and joint position sense from the dorsal columns are left intact.[26]Injury to T12-L2 segmentsmay result in conus medullaris syndrome, while injury to L3-L5 segmentscan lead to cauda equina syndrome. Usually, these syndromes present as incomplete injuries and result in neurogenic bladder and/or bowel, loss of sexual function, and perianal loss of sensation.[28]

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BRENTWOOD, Tenn., Sept. 09, 2022 (GLOBE NEWSWIRE) -- IMAC Holdings, Inc. (Nasdaq: BACK) (IMAC or the Company), today announces it has completed the third cohort of its Phase 1 clinical trial for its investigational compound utilizing umbilical cord-derived allogenic mesenchymal stem cells for the treatment of bradykinesia due to Parkinsons disease.

The third cohort consists of five patients with bradykinesia due to Parkinsons disease receiving an intravenous infusion of a high concentration stem cell treatment. The third and final cohort of the Phase 1 clinical trial was completed on Tuesday, September 6, 2022.

About IMACs Phase 1 Clinical Trial

The Phase 1 clinical trial, consisting of a 15-patient dose escalation safety and tolerability study, is being conducted at three of IMACs clinical centers in Chesterfield, Missouri, Paducah, Kentucky, and Brentwood, Tennessee. The trial is divided into three groups: 1) five patients with bradykinesia due to Parkinsons disease received a low concentration dose, intravenous infusion of stem cells, 2) five received a medium concentration intravenous dose, 3) and five received a high concentration intravenous dose. All groups will be subsequently tracked for 12 months. IMACs medical doctors and physical therapists at the clinical sites have been trained to administer the treatment and manage the therapy. Ricardo Knight, M.D., M.B.A., who is medical director of the IMAC Regeneration Center of Chicago, is the trials principal investigator.

The Institute of Regenerative and Cellular Medicine serves as the trials independent investigational review board, while Regenerative Outcomes provides management of the study. Further details of the trial can be found at clinicaltrials.gov.

About Bradykinesia Due to Parkinsons Disease

In addition to unusually slow movements and reflexes, bradykinesia may lead to limited ability to lift arms and legs, reduced facial expressions, rigid muscle tone, a shuffling walk, and difficulty with repetitive motion tasks, self-care, and daily activities. Parkinsons disease is the typical culprit of bradykinesia, and as it progresses through its stages, a persons ability to move and respond declines.

According to Zion Market Research, the global Parkinsons disease therapeutics market was $2.61 billion in 2018 and is expected to grow to $5.28 billion by 2025. The Parkinsons Disease Foundation estimates that nearly 10 million people are suffering from Parkinsons disease, and almost 60,000 new cases are reported annually in the U.S.

About IMAC Holdings, Inc.

IMAC Holdingsowns and manages health and wellness centers that deliver sports medicine, orthopedic care, and restorative joint and tissue therapies for movement restricting pain and neurodegenerative diseases.IMACis comprised of three business segments: outpatient medical centers, The Back Space, and a clinical research division. With treatments to address both young and aging populations,IMAC Holdingsowns or manages outpatient medical clinics that deliver regenerative rehabilitation services as a minimally invasive approach to acute and chronic musculoskeletal and neurological health problems. IMACs The Back Company retail spinal health and wellness treatment centers deliver chiropractic care within Walmart locations. IMACs research division is currently conducting a Phase I clinical trial evaluating a mesenchymal stem cell therapy candidate for bradykinesia due to Parkinsons disease. For more information visitwww.imacholdings.com.

# # #

Safe Harbor Statement

This press release contains forward-looking statements. These forward-looking statements, and terms such as anticipate, expect, believe, may, will, should or other comparable terms, are based largely on IMAC's expectations and are subject to a number of risks and uncertainties, certain of which are beyond IMAC's control. Actual results could differ materially from these forward-looking statements as a result of, among other factors, risks and uncertainties associated with its ability to raise additional funding, its ability to maintain and grow its business, variability of operating results, its ability to maintain and enhance its brand, its development and introduction of new products and services, the successful integration of acquired companies, technologies and assets, marketing and other business development initiatives, competition in the industry, general government regulation, economic conditions, dependence on key personnel, the ability to attract, hire and retain personnel who possess the skills and experience necessary to meet customers requirements, and its ability to protect its intellectual property. IMAC encourages you to review other factors that may affect its future results in its registration statement and in its other filings with the Securities and Exchange Commission. In light of these risks and uncertainties, there can be no assurance that the forward-looking information contained in this press release will in fact occur.

IMAC Press Contact:

Laura Fristoe

lfristoe@imacrc.com

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The green colors are increased synapses resulting from a regeneration in nerve axons SWNS

A revolutionary treatment that could repair spinal cord injuries has been developed by scientists which regrew nerves in paralyzed mice within three months.

The medication triggers cells of long spindly parts of the severed nerves called axons to regenerative themselves.

Currently, spinal cord injury does not have any effective treatments that involves a repairing of what was damaged. Physical rehabilitation can help patients regain some mobility, and a number of electrical stimulation technologies can stimulate nerves and muscles to act as before, but never with the precision of the real thing.

This work shows a drug called TTK21 that is administered systemically once a week after a chronic spinal cord injury in animals can promote neuronal regrowth and an increase in synapses that are needed for neuronal transmission, said lead author Dr. Simone Di Giovanni, of Imperial College London.

This is important because chronic spinal cord injury is a condition without a cure where neuronal regrowth and repair fail.

Damage to the spinal cord interrupts the constant stream of electrical signals from the brain to the body. It can lead to paralysis below an injury.

The study published in the journal PLOS Biology showed TTK21 aided the regrowth of sensory and motor neurons when given to mice 12 weeks after severe injury.

It belongs to a group of therapies known as epigenetic activators which target damaged DNA.

In experiments, lab rodents with severe spinal cord injury lived in an enriched environment with opportunities to be physically activeas is encouraged in human patients.

Treatment lasted for 10 weeks. Several improvements were identified, the most noticeable being the sprouting of more axons in the spinal cord. Retraction of motor axons above the point of injury was also halted, and sensory axon growth increased.

SIMILAR: Movement in Paralyzed Arms is Restored by Zapping Spinal Cords With Electrical Stimulation

The next step will be to boost the effects even more and get regenerating axons to reconnect to the rest of the nervous system so animals can regain their ability to move with ease.

We are now exploring the combination of this drug with strategies that bridge the spinal cord gap such as biomaterials as possible avenues to improve disability in SCI patients, said Di Giovanni.

For decades, this has remained a major challenge. Our bodys central nervous system, which includes the brain and spinal cord, does not have any significant capacity to repair itself.

RELATED: First Time Someone With Cut Spinal Cord is Able to Walk Freely, Thanks to New Swiss Technology

In the U.S., an estimated 300,000 people and another 50,000 in the UK are living with a spinal cord injury.

Last year GNN reported that Yale had used stem cells to repair patients injured spinal cords, which could be another future avenue to repairing nerves and axons.

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Revolutionary Jab that Could Repair Spinal Cord Injuries Developed by Scientists - Good News Network

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Oxytocin is a neurohormone called the love hormone because it promotes social bonds and generates pleasurable feelings.

It also regulates lactation, uterine contractions, the movement of sperm, and testosterone production.

Now, a new study suggests that the hormone might someday help regenerate damaged heart muscles.

The researchers said that previous research has concluded that the epicardium, a membrane found in the layers of the heart, can partially regenerate injured heart cells. In mammals, however, this process doesnt work independently but might if cells are reprogrammed.

Researchers noted that zebrafish produced oxytocin after their hearts were injured by extreme cold, leading to a response that promotes heart regeneration.

The heart possesses a population of cells, called epicardial cells, that reside in its outer layers, said Aitor Aguirre, Ph.D., one of the authors of the study and an assistant professor of biomedical engineering at the Institute for Quantitative Health Science and Engineering at Michigan State University.

After a massive cardiac injury, such as a heart attack, epicardial cells become epicardial stem cells and can then regenerate muscle, blood vessels, and other cardiac tissues, but their numbers are far too small for any long-lasting impact, he told Healthline.

What we have found in this study is that oxytocin induces the formation of these stem cells and promotes their expansion, increasing their efficiency in heart regeneration, Aguirre added. It is interesting because this demonstrates that the brain controls some regeneration, so there could be factors in addition to the oxytocin that promotes regeneration.

He noted that the most common role of oxytocin relates to bonding and pleasure, which suggests that being in a caring and loving environment might promote heart healing. You could say that the love hormone fixes broken hearts.

Zebrafish are known for their ability to regenerate cells throughout their body.

Past research has reported that these fish can regenerate organs, including the retina, spinal cord, parts of the brain, and certain internal organs. Experts say this makes them a good resource for studying this concept.

The researchers conducting the current study reported that within three days of the heart injury, the Zebrafish increased the expression of oxytocin in the brain by about 18-fold.

The oxytocin then traveled to the epicardium, which bound to the oxytocin receptor, triggering cells to develop new cells. These cells migrated to the myocardium and developed into cardiomyocytes, blood vessels, and other heart cells, replacing the injured ones.

Oxytocin had a similar effect on human cells in a laboratory. The scientists tested 15 neurohormones and they said oxytocin had the strongest effect on stimulating the regeneration of human cells.

Oxytocin is currently used during labor and delivery. It is used to begin or speed up contractions during labor and typically takes effect about 30 minutes after injection. It can also help to reduce bleeding after birth.

The risk of using oxytocin during labor is overstimulation of the uterus and causes it to contract too often, according to the American College of Obstetrics and Gynecology. This may lead to changes in the fetal heart rate.

While there are benefits to using oxytocin during labor and delivery, there are also risks. These risks and benefits will need to be considered as researchers look at the hormones potential use for stimulating heart regeneration.

Oxytocin, or a similar analog that stimulates its receptor, could conceivably be utilized to regenerate the heart in humans after acute or chronic injury, said Dr. Rigved Tadwalkar, a cardiologist at Providence Saint Johns Health Center in California.

The current study reveals the beneficial effects of oxytocin in zebrafish in vivo and on human tissue in vitro, Tadwalkar told Healthline. The findings suggest that the pathway involved in stimulating stem-like cells to the myocardium is preserved in humans, at least to a degree.

Unfortunately, oxytocin has a short half-life, meaning that it exists only briefly in human circulation, Tadwalkar added. However, we could take advantage of this beneficial signaling pathway in humans by creating drugs that are higher in potency or with longer half-lives.

Since we already use oxytocin clinically, this is not inconceivable, he noted. Even if the effects are limited, the benefit would be splendid in this population. For example, if oxytocin is shown to only have a preventative role, as opposed to a regenerative one, this would still be welcome, as to avert subsequent damage to the heart.

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Neuron generation trajectories. Credit: BGI Genomics

Because of its distinctive and adorable look, the axolotl Ambystoma mexicanum is a popular pet. Unlike other metamorphosing salamanders, axolotls (pronounced ACK-suh-LAH-tuhl) never outgrow their larval, juvenile stage, a trait known as neoteny. Its also recognized for its ability to regenerate missing limbs and other tissues including the brain, spinal cord, tail, skin, limbs, liver, skeletal muscle, heart, upper and lower jaw, and ocular tissues like the retina, cornea, and lens.

Mammals, including humans, are almost incapable of rebuilding damaged tissue after a brain injury. Some species, such as fish and axolotls, on the other hand, may replenish wounded brain regions with new neurons.

Tissue types the axolotl can regenerate as shown in red. Credit: Debuque and Godwin, 2016

Brain regeneration necessitates the coordination of complex responses in a time and region-specific way. In a paper published on the cover of Science, BGI and its research partners used Stereo-seq technology to recreate the axolotl brain architecture throughout developing and regenerative processes at single-cell resolution. Examining the genes and cell types that enable axolotls to renew their brains might lead to better treatments for severe injuries and unlock human regeneration potential.

Cell regeneration images at seven different time points following an injury; the control image is on the left. Credit: BGI Genomics

The research team collected axolotl samples from six development stages and seven regeneration phases with corresponding spatiotemporal Stereo-seq data. The six developmental stages include:

Through the systematic study of cell types in various developmental stages, researchers found that during the early development stage neural stem cells located in the VZ region are difficult to distinguish between subtypes, and with specialized neural stem cell subtypes with spatial regional characteristics from adolescence, thus suggesting that various subtypes may have different functions during regeneration.

In the third part of the study, the researchers generated a group of spatial transcriptomic data of telencephalon sections that covered seven injury-induced regenerative stages. After 15 days, a new subtype of neural stem cells, reaEGC (reactive ependymoglial cells), appeared in the wound area.

Axolotl brain developmental and regeneration processes. Credit: BGI Genomics

Partial tissue connection appeared at the wound, and after 20 to 30 days, new tissue had been regenerated, but the cell type composition was significantly different from the non-injured tissue. The cell types and distribution in the damaged area did not return to the state of the non-injured tissue until 60 days post-injury.

The key neural stem cell subtype (reaEGC) involved in this process was derived from the activation and transformation of quiescent neural stem cell subtypes (wntEGC and sfrpEGC) near the wound after being stimulated by injury.

What are the similarities and differences between neuron formation during development and regeneration? Researchers discovered a similar pattern between development and regeneration, which is from neural stem cells to progenitor cells, subsequently into immature neurons and finally to mature neurons.

Spatial and temporal distribution of axolotl brain development. Credit: BGI Genomics

By comparing the molecular characteristics of the two processes, the researchers found that the neuron formation process is highly similar during regeneration and development, indicating that injury induces neural stem cells to transform themselves into a rejuvenated state of development to initiate the regeneration process.

Our team analyzed the important cell types in the process of axolotl brain regeneration, and tracked the changes in its spatial cell lineage, said Dr. Xiaoyu Wei, the first author of this paper and BGI-Research senior researcher. The spatiotemporal dynamics of key cell types revealed by Stereo-seq provide us a powerful tool to pave new research directions in life sciences.

Corresponding author Xun Xu, Director of Life Sciences at BGI-Research, noted that In nature, there are many self-regenerating species, and the mechanisms of regeneration are pretty diverse. With multi-omics methods, scientists around the world may work together more systematically.

Reference: Single-cell Stereo-seq reveals induced progenitor cells involved in axolotl brain regeneration by Xiaoyu Wei, Sulei Fu, Hanbo Li, Yang Liu, Shuai Wang, Weimin Feng, Yunzhi Yang, Xiawei Liu, Yan-Yun Zeng, Mengnan Cheng, Yiwei Lai, Xiaojie Qiu, Liang Wu, Nannan Zhang, Yujia Jiang, Jiangshan Xu, Xiaoshan Su, Cheng Peng, Lei Han, Wilson Pak-Kin Lou, Chuanyu Liu, Yue Yuan, Kailong Ma, Tao Yang, Xiangyu Pan, Shang Gao, Ao Chen, Miguel A. Esteban, Huanming Yang, Jian Wang, Guangyi Fan, Longqi Liu, Liang Chen, Xun Xu, Ji-Feng Fei and Ying Gu, 2 September 2022, Science.DOI: 10.1126/science.abp9444

This study has passed ethical reviews and follows the corresponding regulations and ethical guidelines.

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Unlocking the Mysteries of Brain Regeneration Groundbreaking Study Offers New Insight - SciTechDaily

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Chronic pain, a disease process that is so complex that we are only just beginning to understand its triggers, has recently been gaining recognition as a medical condition on its own. But how does living with chronic pain feel? And how do the body and brain deal with it?

Aching, dull, gnawing, burning, sharp, shooting, piercing

These are just some of the words people tend to use to describe their pain.

Now imagine you had to endure a bit of this every waking day until you dont know what its like to go about your day without this baseline of pain slowly depleting your mental and physical energy in the background.

That is the reality for many people who deal with chronic pain.

Some days may be great, some days bad; the signs may not always be visible and it may be an inward battle hidden behind gritted teeth and forced smiles.

But how does chronic pain become, well, chronic?

In the latest installment of our In Conversation podcast dedicated to Pain Awareness Month, Medical News Today dives into the science behind chronic pain with Dr. Hilary Guite and Dr. Tony L. Yaksh, professor of anesthesiology and pharmacology at the University of California, San Diego, as Joel Nelson, longtime psoriatic disease and arthritis patient and advocate, shares his personal journey with pain.

Chronic pain may often be dismissed as purely a symptom of a larger problem or not taken as seriously because it is not life threatening. However, the burden of chronic pain is not only personal but also societal.

Studies show that people with chronic pain may have difficulty in going about their daily lives and doing activities, as well as have poorer overall health. People with chronic pain may also have to deal with job insecurity or unemployment.

It wasnt until 2018 that the International Classification of Diseases (ICD) gave chronic pain its own code, in the preliminary version of the new ICD-11 coding system, paving way for its recognition and diagnosis.

According to the World Health Organization (WHO), chronic pain is now classified into two categories: chronic primary pain and chronic secondary pain.

Primary pain, according to this classification, refers to pain that is not caused by or cannot be explained by another medical condition. Some examples may be fibromyalgia or chronic primary low back pain.

Fibromyalgia [is] a condition that varies from person to person, but is a widespread pain condition affecting at least 4 to 5 regions of the body and lasts at least 3 months but usually longer. No other cause is found for the pain and it is, therefore, a type of primary chronic pain, Dr. Guite explained.

Secondary pain, on the other hand, is secondary to or caused by an underlying medical condition. Arthritis, cancer, or ulcerative colitis-related pain would fall within this umbrella.

[M]y chronic pain started around 10 years old. And [since] then, chronic pain has kind of been an intermittent part of my life right through to the present day, Joel Nelson told MNTs In Conversation.

Joel is now 38 years old, which means hes been living with chronic pain for a good few decades.

[M]y first experience with pain was [when] I got a pain in my hip; it was like a gravelly sort of burning feeling. And it just progressed; the more I used the joint, the [more it got] worse, it got to the point where I [was] sort of losing mobility, he said.

That was the point he decided to reach out for helpas most people do.

Joel said one word to describe his chronic pain is noise.

I always have described it as noise because on the days when that pain is intense, my ability to absorb other information, deal with multiple things at a time, its just gone, he said.

Living with my condition today, I think the most important takeaway about the experience is the fluidity of it. [U]ltimately, [my limits and mobility] can range from anything to where I can do more than walking, and I might be able to do a bit of running and cycling like I am currently, to next week I might be back on crutches. [A] lot of that is dictated by pain. So with arthritis, I get a lot of morning stiffness, but its the pain that limits my ability to do things. Joel Nelson

Likening it to a series of chapters, Joel said its not easy to anticipate what will happen next with his chronic pain.

Behind acute pain becoming chronic, scientists have found that a gateway receptor called Toll-like receptor 4 (TLR4) may be a controlling factor.

We know that under a tissue [or nerve] injury of various sorts that we can activate signaling that normally is associated with what we call innate immunity. And one of the mediators of that is something called the toll-like receptor and it turns out that while those are normally there to recognize the presence of foreign bugs, for example, E. coli, those bugs have in their cell membrane, something called lipopolysaccharide, or LPS. We dont have that normally in our system, but it comes from bacteria, said Dr. Yaksh.

Youre born with it, you dont have to develop it. Its there all the time. What weve come to find out over the last years [t]hat there are many products that your body releases that will [a]ctivate those very same toll-like receptors, he added.

Toll-like receptors may prime the central immune system for heightened states of pain. In response to harmful stimuli, stressors, or tissue injury, especially in the microbiome or the gastrointestinal tract, the body starts to release products from inflammatory cells.

When this happens, these products that are released from our own body can [a]ctivate these toll-like receptors, and theres [one] we call TLR4 [which] is present on inflammatory cells, and its also present on sensory neurons, he explained.

Dr. Yaksh said that activating TLR4 itself doesnt cause as much pain, but that it sets the nervous system up to become more reactive.

Coupled with this priming, if there are other stressors present at the timesuch as a bad diet or psychological distress, pointed out Dr. Guite this can set off a whole cascade that can fuel this transition to chronic pain.

[The activation of TLR4] sets up a whole series, a cascade in which there will be an increased expression of a large number of receptors and channels that are able to drive an enhanced response of the system. When this happens, you get this enhanced response downstream to the initial tissue injury. Its not so much that [it] causes the pain condition, it just sets the system up to be more reactive. Dr. Tony Yaksh

He said Joels situation fits within the notion that a person can transition from one type of pain to another.

[T]hat can be exacerbated by the stresses that are psychological which can exacerbate a pain state to one that may, in fact, have an underlying physiological component that we may not really understand, he added.

In Joels case, for example, Dr. Yaksh suggested it was likely that the stress (and joy) of becoming a father and all the other aspects played a role in what exacerbated Joels condition, and made it harder to keep the pain under control. He stressed that this did not make the pain any less real.

I think that probably there was this very strong, emotive component thats associated what Joels situation was, [] that the pain condition and the events that were associated with the psoriatic diagnosis and other aspects, perhaps, in fact, did establish the transition from one state to another [what] we call a transition or an acute to chronic, or the chronification of the pain state, he elaborated.

Theories so far suggest pain happens at the intersection of where the body meets the brain.

[Y]our comment about pain [being] in the brain is absolutely the correct way to think about it; the output function of anything comes from the higher centers, said Dr. Yaksh.

It all boils down to how the brain registers pain when there is tissue damage.

Pain is a crucial function for our survival; it is essentially a warning system that alerts our bodies that there is damage or illness to deal with. After an illness or injury, the nerves surrounding the area start sending signals up to the brain through the spinal cord, which encourages us to get help and stop further damage.

After the body sustains an injury, the damage to the bodys organs and tissues triggers an acute inflammatory response that involves immune cells, blood vessels, and other mediators. However, sometimes, even after this initial injury phase passes and the body heals, the nervous system may stay in this state of distress or reactivity.

When this happens, the body may become hypersensitive to pain. If this increased sensitivity is to heat or touch around the injured area, this is called peripheral sensitization.

[I]f I were to jam my finger, or if I were to develop, in Joels case, an event that leads to a local autoinflammation of the joint, then, in fact, that inflammation leads to the release of factors, which now sensitize the innervation of that joint, Dr. Yaksh elaborated.

Dr. Yaksh said this is something all people experience, regardless of whether it is chronic pain. He explained that after an injury, however, an innocuous activity such as wiggling ones finger can [become] extraordinarily noxious.

He described this as a sensitization generated by peripheral injury and inflammation, where this information is then relayed to the brain through the spinal cord.

The brain is now seeing what is otherwise an innocuous event, generating a signal that looks as if, as we would say, hell has frozen over, bad news is coming up the pipe. Dr. Tony Yaksh

However, sometimes this prolonged response to the initial injury may cause the lingering pain to be widespread, rather than localized to the injured area. This is called central sensitization.

[I]ts interesting in [Joels case], that you clearly have a peripheral issue, whether its the inflammation of a joint, inflammation of the skin, or changes in peripheral nerve function. And so not only do you get changes in joint morphology and things of that sort, but you actually get changes that lead to changes in the way that the information that goes into the spinal cord, and then to higher centers, Dr. Yaksh explained, and youve activated specific populations of sensory fibers that are normally activated only by severe injury.

[I]ts possible for that spinal cord, which is now, in a sense, organizing the input-output function from the periphery to the brain can become reorganized very much like if I were to take a radio and turn the volume upthe signal to the radio hasnt changed, but the volume gets louder. So, think of the spinal cord as a volume regulator. Dr. Tony Yaksh

And it says, bad news has happened. But we now know actually, that some of that input that comes up the same pathway [g]oes to areas of the brain that has nothing to do with where that pain [comes] fromonly that it is intense, he said.

These outputs that travel up the spinal cord inform the brain of where and how intense the pain is. One area these are processed in is the limbic system, or the old smell brain, said Dr. Yaksh.

These are areas of the brain that are, in fact, associated in humans with the input associated with emotionality, he added.

This stress can also modulate how pain is perceived by the body; it can cause muscles to tense or spasm, as well as lead to a rise in the levels of the hormone cortisol. This may cause inflammation and pain over time.

This can, in turn, can lead to sleeping problems, irritability, fatigue, and depression over time, creating a vicious cycle that adds to an already stressed nervous system, worsening the pain.

Although treatments for acute pain often involve taking various medications such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), or opioids, treatment and management strategies for chronic pain are quite limited.

[W]e started out this conversation by saying pain is in the brain. And your perceptions of what the world is about impact you very directly, and in a way that is actually experimentally definable, changes the way your brain reacts. So when I say pain is in the brain, I am not saying its, its any less real in any way, shape, or form. Its a real thing, said Dr. Yaksh.

We now teach medical students that, you know, just because you dont see the primary diagnosis as being a swollen joint doesnt mean the patient doesnt have something, he pointed out.

Dr. Yaksh said mindfulness is often used in therapy to treat or manage fibromyalgia. He said that this doesnt mean there is no physiological component of fibromyalgia and indeed, recent research has shown that it is very likely to be an autoimmune condition just as real as the presence of antibodies that define the presence of an arthritic joint, he said.

Mindfulness, in a way, can help the individual respond to the nature of the afferent traffic thats coming up the spinal cord; its not something you could become mindful enough to say have surgery done. But it might [t]ake the edge off of some of the things that are, in fact, driving this exaggerated response. Fibromyalgia is a perfect example. Dr. Tony Yaksh

[Mindfulness] doesnt make the pain state any less real [but it] demonstrates that changing the way you think about your pain condition [can] help you deal with that pain condition, he said.

Joel added that, from the perspective of someone with chronic pain, it is a journey to see how the brain and the body work together to maintain pain:

.[I]t is a really delicate conversation when you talk about pain and it residing in the brain and, as somebody whos gone full circle through that journey of being horrified when that was first suggested to going through pain management, and then understanding it so that I could process it better. It changed everything for me.

What the future holds for treating chronic pain currently remains unclear. However, hope is that drugs might be developed to impact receptors such as TLR4 in a way that might not result in the pain going from acute to chronic, and that our understanding of how psychological processes interact with the neuro-immune interface increases over time.

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Most of us are familiar with the scientific fact that any living, breathing animal, insect etc. is made up of cells. These cells form tissues and organs that support the existence of the host. Many of us have also heard of stem cells therapy for autism but are unsure about its validity.

Scientists have studied the underlying mechanism of cells, as well as their functioning, and have discovered ways of using the cells to improve the lives of humans and treat diseases. To do so, scientists have discovered stem cells; think of it as the building blocks of a fully differentiated cell.

Stem cells are human cells that can be developed and differentiated into other cell types. These cells can be derived from any part of the body, for example, stem cells from the brain, muscle, bone marrow, etc. Stem cells are versatile in that they can be used to fix damaged tissues. The two essential characteristics of stem cells include: Firstly, the ability to self-renew to create successors identical to the original cell. Secondly, stem cells, unlike cancer cells, are controlled and highly regulated, therefore, stem cells need to be able to give rise to specialized cell types that become part of the healthy body.

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The purpose of stem cell therapy is to regenerate and repair damaged tissues and cells in the body. There are two main classes of stem cells. Pluripotent stem cells have the potential to become any cell in the adult body and multipotent stem cells are much more restricted to a specific population or lineage of cells. Other stem cell types include totipotent and unipotent.

Lets look at pluripotent and multipotent stem cells in detail.

Pluripotent stem cells are generated from somatic cells. These mainly come from embryos and, as such, theyre often referred to as embryonic stem cells.

Lets discuss three types of embryonic stem cells that are used to generate pluripotent cells. These include true embryonic stem cells (ES), nuclear transfer of somatic cells (ntES), and parthenogenetic embryonic stem cells (these are stem cells from unfertilized eggs).

The true embryonic stem cells are made from unused embryos, such as those that undergo IVF (in vitro fertilization). The process of IVF is such that the eggs and sperm are fertilized in a lab dish. What then happens is that, through this process, more embryos are generated, usually more than the couple actually need. Those that arent used can be donated to science.

Pluripotent cells made from these unused embryos are not genetically matched to the original hosts. These are mainly used in science for studies to learn how stem cells regenerate.

Every cell contains an organelle called a nucleus. The nucleus contains all the cells genetic information essential to its function. The word somatic refers to any cell in the body.

The process of somatic cell nuclear transfer (SCNT) extracts the nucleus from a somatic cell and transfers it into another cell that has had its own nucleus removed; i.e. the nucleus from the previous cell is being transferred to an egg cell that does not contain a nucleus (unnucleated).

When the nucleus is transferred to another cell, it activates the process of pluripotent cell generation that reprograms the generation of genes in that cell. The egg then becomes a zygote nucleus or a fertilized egg, the cell then replicates and through it embryonic stem cells are created.

Imagine being able to fertilize an egg without fertilization by sperm. Unusual, but science makes crazy things happen.

Parthenogenesis is the process whereby an unfertilized egg develops an embryo without fertilization. This can be achieved through chemical, physical or combined activation methods.

The parthenogenetic embryonic stem cells have the capacity for infinite proliferation and self-renewal, and maintain the ability to differentiate into one or more specialized types of cell or tissue.

pESCs are especially useful for regenerative medicine, and therefore allow the generation of functional cells that could potentially be used as treatment for many incurable diseases in the future.

Multipotent stem cells are unspecialized cell types that have the ability to self-renew and differentiate into specialized cell types. However, these cells are specific to the type of tissue or organ. For example, a multipotent adult stem cell from the bone marrow can become specialized to produce all blood cell types; and cells in the stem cells from neural networks in the brain can specialize to glial and neuronal cells.

When we talk about all blood cell types, we have to get a little scientific, but for the curious mind, all blood cell types refers to platelets, B and T lymphocytes, natural killer cells, dendritic cells.the list goes on.

In addition, for the curious mind, various types of stem cells include hematopoietic stem cells (the ones that make blood cell types), mesenchymal stem cells (differentiate into bone, fat, cartilage, muscle, and skin), and neural stem cells (from neural networks).

Now that weve covered the types of stem cells, the question remains, can stem cell therapy cure autism? Lets have a look.

To answer this question, I refer to the review by Price (2020) as it is the latest up-date data on this subject. It is important to note however, that at the time of reading this article there may be other research data published on this topic.

Several research studies cite immune dysfunction as the cause and effect of autism spectrum disorder (ASD). By virtue of this analogy, it has informed the basis of the stem cell therapy approach for treating autism. This is founded on the properties that regulate the immune system (immuno-regulatory properties).

From the review, it was also found that when exposed to inflammatory stimuli, this may lead to the development of postnatal diagnosis of ASD. Inflammation to the cell describes the process that occurs when the cell is exposed to harmful stimuli such as bacteria, trauma, toxins, heat, and pathogens. The affected cells then release chemicals that cause blood vessels to leak fluid into the tissues, causing swelling.

Therefore, an inflammatory stimuli is that which influences the occurrence of an inflammatory response.

Other bodies of research found an altered level of proteins called cytokines which are essential for interaction and communication between cells in ASD. These may also be the cause of the development of autism spectrum disorder. Some genetic studies propose an association between a genetic loci (a specific point on the genome of the autistic individual) and ASD whose function is related to immune function. While others suggest a possible anomaly in the neuronal signaling pathway that directs communication and information transfer between neurons

All these are proposed reasons that hypothesize the use of stem cell therapy to treat autism biologically. However, all these propositions do not lead to one voice, there are too many hypotheses that make it difficult to narrow down the target area that would potentially treat autism or autism symptoms. Keeping in mind that autism traits are diverse, therefore, narrowing this information down to one plausible pathology is an even greater challenge.

So, is stem cell therapy effective? The answer to this is unknown.

Is ASD caused by genetic, immune dysfunction, or inflammatory stimuli? The answer to this is not clear and theres a vast number of studies that argue different theories.

It is even more disturbing to consider these hypotheses because, for example, each person can experience bacterial or viral infections, or stress that can impact immune functioning and/or lead to inflammation but were not all on the spectrum. Therefore, we cant say that factors which alter our immune functioning lead to the development of neurodevelopmental conditions.

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However, according to Price, the study by Riordan et al. (2019) proposes the influence of cytokines for the treatment of autism.The data proposed could be a point in a positive direction to answering whether stem cell therapy could potentially treat autism symptoms.

Unfortunately, there is no data to positively state the effectiveness of stem cell therapy for treating autism. As more research is developed in this field, theres hope that more understanding of autism will arise, and perhaps an alternative form of treatment of autism symptoms can be developed. It is also worth noting the possibility of genetic markers that could help diagnose autism during pregnancy or during the prenatal development stage.

The studies highlighted in this article are simply preliminary assessments. Further research needs to be conducted in order to understand the potential of cell therapies for treating autism.

The findings of these studies vary in hypothesis and this makes generalization hard. Science has developed greatly over years, therefore, for those that believe in the potential of science and all that it could offer, theres a reason to hope that stem cell therapy could potentially be used as treatment for autism in the near future.

Biehl, J. K., & Russell, B. (2009). Introduction to stem cell therapy. The Journal of cardiovascular nursing, 24(2), 98105. https://doi.org/10.1097/JCN.0b013e318197a6a5

Price, J.(2020). Cell therapy approaches to autism: a review of clinical trial data. Molecular Autism, 11, 37 . https://doi.org/10.1186/s13229-020-00348-z

http://stemcell.childrenshospital.org/about-stem-cells/adult-somatic-stem-cells-101/where-do-we-get-adult-stem-cells/

Thermo Fisher Scientific. An Overview of Pluripotent and Multipotent Stem Cell Targets. https://www.thermofisher.com/za/en/home/life-science/antibodies/antibodies-learning-center/antibodies-resource-library/antibody-methods/pluripotent-multipotent-stem-cell-targets.html

Yu, Z., Han, B. (2016). Advantages and limitations of the parthenogenetic embryonic stem cells in cell therapy. Journal of Reproduction and Contraception, 27 (2), Issue 2, 118-124. https://doi.org/10.7669/j.issn.1001-7844.2016.02.0118

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Stem Cells Therapy for Autism: Does it Work?

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Figure 2.. CD39 - CD69 - CD8 + TILs in infusion product are in a

(A) t-SNE plot of all CD8+ TILs from CR and NR I.P. (5 CRs, 5 NRs). (B) Frequency distribution of each cluster (1 through 8) expressed as a % of total CD8+ T cells in the I.P. for each patient. (C) Data points representing % of S.Cluster.A (top) and % of S.Cluster.B (bottom) per each patient I.P. between CRs and NRs. S.Cluster.A encompasses clusters C0, C2, C5, C6, and C7; S.Cluster.B comprises clusters C1, C3, C4, and C8. P-values by two-sided Wilcoxon rank-sum test are shown. (D) Heatmap of top 15 discriminating genes between S.Cluster.A and S.Cluster.B displayed for each cell. All discriminating genes are listed in Table S4. (E) t-SNE plot of clustered cells displayed by the top two quartiles of CD39-CD69- (DN) gene signature expression, and top two quartiles of CD39+CD69+ (DP) gene signature expression. (F) Each patient I.P. was scored by DN and DP gene signature scores and their mean scGSEA values are plotted. CRs are in red, and NRs are in black. P-values by two-sided Wilcoxon rank-sum test comparing the mean DN and DP signature scores between CRs and NRs are shown. (G) Flow cytometric analysis of inhibitory and memory markers within each subset (DN [CD39-CD69-], SP [CD39-CD69+, CD39+CD69-] and DP [CD39+CD69+] of patient I.P. in the validation set (n=38) expressed as % of each subset (parent gate). * P < 0.05 **P < 0.01 ***P < 0.001 ****P < 0.0001 by Tukeys multiple comparison test. (H) Flow cytometry of intracellular TCF7 expression for DN and DP subsets showing representative patient I.P. sample (top) and quantitation for 18 I.P. (bottom). P-value by two-sided Wilcoxon rank-sum test is shown. (I) Phenotypes of DN, SP, and DP states before and after CD3/CD28 stimulation at 48 hours showing flow cytometry plot in a representative patient sample (left) and summary of daughter cells in each state after stimulation of 6 patient I.P. (right). ***P < 0.001 by two-sided Wilcoxon rank-sum test. (J) t-SNE clusters of CD8+ TILs from Melanoma ICB cohort (15) (K) t-SNE plot colored by top two quartiles of DN and DP gene signatures, DN: red, DP: black (L) TILs from pre ICB therapy were scored by the top DN and DP gene signature scores and mean scGSEA scores are plotted. Cells from responding lesions are in red, and cells from progressing lesions are in black. Cell numbers and P-values by two-sided Wilcoxon rank-sum test are shown. (M) Clustered correlation matrix of gene signatures from other studies (Table S5) along with DN and DP scGSEA scores on pre-ICB cells from the cohort.

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Looking for that bright-eyed look? Here you go!

If there's one overlooked aspect of a persons skincare routine, it is moisturising the under eyes. The middle child of the skin care routine, oftentimes applying this product is overlooked for a full coverage concealer. Your deepening dark circles aren't thanking you for those sleepless nights spent binge watching your favourite comfort shows after a long, hard day at work. Eye creams are your best friend when it comes to wanting to look like you have your life together the next day at 9 am in the office. From depuffing to helping fade dark circles, fine line reduction and hydrating the delicate skin of your under eye, you name it, these products do it!

The Dear, Klairs Fundamental Nourishing Butter provides the essential moisture needed for the under eye and special antioxidant care for those battling dryness. So you can bid a happy adieu to fine lines and dark circles while also boosting the inherent elasticity of your skin. As its name rightfully suggests, its soft butter-like consistency easily absorbs into the skin to moisturise and brighten the under eyes. With the goodness of Vitamin A and E,quad peptide as well as sunflower seed oil to protect the delicate skin of our eyes, this nourishing eye butter goes well under your makeup giving you a smooth base like no other. Additionally, this cream can also be applied on the neck and nasolabial folds to reduce the appearance of fine lines.

Avocado in your smoothies, salads, face packs and now once again the glorious avocado in your eye cream. An eye cream with potent ingredients for skin that is dehydrated. The Kiehls Creamy Eye Treatment with Avocado is an excellent choice to give your skin radiance and make your eyes appear more alert. Shea Butter, Avocado Oil, and Beta-Carotene, a naturally derived antioxidant that is found in carrots and oranges and is known to sharpen the eye sight ,are used in its formulation to keep your skin moisturised and hydrated all day. These substances' qualities also combat ageing symptoms including wrinkles and fine lines. Excellent for all skin types!

The Innisfree Black Tea Youth Enhancing Eye Serum is a powerful product that reduces fine lines and wrinkles and camouflages signs of fatigue around the eyes. The serum emulsifies active components into the skin to nourish it back to health. With a brownie point earned for no stickiness left, it is brightening and highly nourishing in its make up. The exclusive innisfree green tea ( formulated after intense research) is fermented to make the star ingredient of this product the black tea. The Black Tea is then steeped in mineral water for 12 hours to extract all of the potent antioxidants and anti-aging ingredients. Reset Concentrate, a powerful active component, was produced using this exclusive extraction technique.

The Daughter Earth microemulsion under eye serum is a power packed eye serum that incorporates the Ayurvedic Super Triad- amalaki, haritaki and bibhitaki, popularly known as Triphala. Using modern scientific breakthrough apple stem cell technology and probiotics, this under eye serum will moisturise and nourish the sensitive skin of your undereyes with 8 Super Fruits, 5 Peptides, 3 Ceramides and 8 Amino Acids in a lightweight and potent formula. Its ingredients are tailor made to give you the most benefit. Caffeine, Quinoa and the skin loving ingredient niacinamide work towards eradicating dark circles and depuffing the eyes. Plant stem cells reduce fine lines and peptides and wild roselle make your skin supple and firm.

Enriched with the power of Anise, the Forest Essentials Intensive Eye Cream incorporates an Innovative formulation created especially for the delicate eye area. Papaya and potato starch active extracts aid in minimising the appearance of dry and dehydrated lines. It reduces the stubborn appearance of dark circles, fine lines, and dull skin. Along with sweet, cold pressed almond oil that deeply moisturises and adds a glow to the skin, the cream also has properties of cucumber in it that leads to reduced pigmentation and blemish free skin. With consistent use, the eye area becomes more brilliant and clear thanks to anise and chakshushya.

The Shiseido Ultimune Power Infusing Eye Concentrate combats signs of ageing and drooping skin and defends your delicate under eyes against damage in one application. If you're guilty of scrubbing your eyes till you see all black like me this serum is made for you. It heals your skin against the harsh friction and other environmental factors and is the perfect pre-treatment before your eye serums to give that extra boost to your daily skincare.

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6 Under Eye Products You Need To Have STAT - Grazia India

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OverviewWhat is bone marrow?

Bone marrow is the soft, fatty tissue inside of bone cavities. Components of your blood including red and white blood cells and platelets form inside of your bone marrow.

Bone marrow makes nearly all the components of your blood. It's responsible for creating billions of red blood cells daily, along with white blood cells and platelets. Bone marrow also stores fat that turns into energy as needed.

Bone marrow makes the components of your blood that you need to survive. Bone marrow produces red blood cells that carry oxygen, white blood cells that prevent infection and platelets that control bleeding. The absence of bone marrow can be fatal since it's an essential part of your body.

Yes, bone marrow and the healthy cells it produces are necessary for humans to live. Often, cell mutations harm healthy bone marrow cells, and a bone marrow transplant would be a treatment option for people diagnosed with blood cancers like leukemia.

A bone marrow transplant takes healthy cells from a donor and puts them into your bloodstream. The donors cells help your body grow healthy red and white blood cells and platelets.

There are three parts to the anatomy of your bones: compact bone, spongy bone and bone marrow. Compact bone is the strong, outer layer of your bones. Spongy bone makes up the ends of your bones. Bone marrow is in the center of most bones and in the end of spongy bones in your body. Bone marrow and blood vessels fill cavities in your bones, where they store fat and stem cells and produce blood cells that make your whole blood.

Bone marrow is a spongy, soft tissue that resembles a jelly or jam that you would spread on toast. It comes in two colors, red and yellow. Bone marrow fills the cavities of your bones and holds cells that create red and white blood cells and platelets, which make whole blood. The color of red bone marrow is the result of red blood cell production.

There are two types of bone marrow in your body, which are characterized by their color. Your body holds just under 6 lbs. (about 2.5 kg.) of red and yellow bone marrow.

Red bone marrow makes up all of your bone marrow until about age seven. Yellow bone marrow gradually replaces red bone marrow as you age.

Bone marrow is made of stem cells. These stem cells make red bone marrow, which creates blood cells and platelets for your blood. Yellow bone marrow consists mostly of fat and stem cells that produce bone and cartilage in your body.

Directly targeting bone marrow is leukemia, which is a blood and bone marrow cancer. Leukemia forms when a cell mutation occurs in your bone marrow and mutated cells multiply out of control, reducing the production of healthy, normal cells.

Since bone marrow is the foundation for the creation of blood cells, blood-related conditions often are the result of abnormally functioning bone marrow. These conditions include:

Common symptoms of bone marrow conditions include:

There are two tests to check the health of your bone marrow and/or blood cells:

For a bone marrow test or donation, youll receive an anesthetic, so you won't feel any pain during the procedure. After the procedure, you may feel side effects, which include aches and pain at the site of the incision. Each individual experiences pain differently, so the severity could vary from person to person. The pain may last for a few days or up to several weeks.

Treatments for bone marrow conditions vary based on the severity and progress of the diagnosis. Treatment options include:

Bone marrow is the foundation of your bones, blood and muscles. Keeping your bone marrow healthy focuses on supporting components of your body that grow from bone marrow cells. You can keep your bone marrow healthy by:

A note from Cleveland Clinic

Bone marrow is the soft center of the bones in your body. Bone marrow is necessary to create components of your blood and store fat. The best way to keep your bone marrow healthy is to support the parts of your body that your bone marrow produces, like your blood, muscles and bones.

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Bone Marrow: What it is & Why it is Important - Cleveland Clinic

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We explain a protocol for straightforward isolation and culture of mesenchymal stem cells (MSCs) from mouse bone marrow (BM) to supply researchers with a method that can be applied in cell biology and tissue engineering with minimal requirements. Our protocol is mainly on the basis of the frequent medium change in primary culture and diminishing the trypsinization time. Mouse mesenchymal stem cells are generally isolated from an aspirate of BM harvested from the tibia and femoral marrow compartments, then cultured in a medium with Dulbecco's modified Eagle's medium (DMEM) and fetal bovine serum (FBS) for 3 h in a 37 degrees C-5% CO(2) incubator. Nonadherent cells are removed carefully after 3 h and fresh medium is replaced. When primary cultures become almost confluent, the culture is treated with 0.5 ml of 0.25% trypsin containing 0.02% ethylenediaminetetraacetic acid for 2 min at room temperature (25 degrees C). A purified population of MSCs can be obtained 3 weeks after the initiation of culture.

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As cancer treatments continue to advance and new therapies are introduced, it's easy to get lost in your search for information. To help you better understand the differences between specific cancer treatments and how they work, we spoke with medical oncologist Bhavina Sharma, MD, MPH.

"Chemotherapy are drugs designed to directly attack all rapidly dividing cells in the body, including cancer cells," explains Dr. Sharma. "It relies on the idea that cancer cells reproduce much faster than most healthy cells in our body."

Chemotherapy drugs can be given by infusion or in pill form. Unfortunately, these drugs can't tell the difference between cancerous cells and fast-growing healthy cells like the gastrointestinal tract and hair follicles, leading to side effects such as diarrhea and hair loss. Thankfully, recent advancements in chemotherapy have helped lessen side effects such as nausea, pain and lethargy.

Targeted therapy are special drugs designed to target differences within cancer cells that help them thrive. Unlike chemotherapy, targeted therapy drugs actually change the inner workings of the cancer cell. Because targeted therapy focuses on the part of the cancer cell that makes it different from the normal, healthy cell, it often has fewer side effects than standard chemotherapy treatments.

Immunotherapy is very different than chemotherapy in that it helps our immune system to find and kill cancer cells.

"Cancer cells are abnormal cells that have formed in our body because of cell damage or mutations," explains Dr. Sharma. "Cancer cells hide from your immune system by shutting down certain pathways of the immune response. Immunotherapy unlocks those pathways so your immune system can recognize and remove the cancer cells."

Cellular therapies are treatments that improve the body's ability to fight cancer. "Stem cell therapy falls under the umbrella of cellular therapy," explains Dr. Sharma. "It uses stem cells to mount an immune response to attack your cancer cells."

Stem cells from blood and bone marrow can be used in transplants. These stem cells can either come from a matched donor (allogeneic) or from the patient themselves (autologous).

Chimeric antigen receptor therapy or CAR T-cell, is a type of cellular therapy.

"T cells are white blood cells that help our bodies fight infection and cancer," explains Dr. Sharma. "With CAR T-cell therapy, your own T cells are collected from your blood. These T cells are modified to recognize cancer as a foreign cell and attack it."

CAR T-cell therapy has been approved by the Food and Drug Administration to treat lymphoma, leukemia and multiple myeloma.

Hormone therapy slows or stops the growth of cancer that uses hormones to grow. It is also called hormonal therapy, hormone treatment or endocrine therapy. Hormone therapy is recommended for cancers that are hormone-receptor positive, such as certain breast and prostate cancers. It can't be used in cancers that don't carry hormone receptors.

"Hormone therapy can be used for both early stage and metastatic hormone-receptor positive breast cancers," explains Dr. Sharma. "In patients with early-stage breast cancer, it is used after surgery to help reduce the risk of the cancer coming back."

Chemotherapy, immunotherapy, targeted therapy, and hormone therapy are just a few of the treatments we use to treat cancer. Many of these cancer treatments can be combined with others like cancer surgery and radiation therapy. Every person's journey through cancer is different. Your oncology team will help you sort through the best therapies available to create your treatment plan.

The information in this article is for information purposes only. For specific questions regarding your medical condition or treatment plan, please consult with your doctor directly. To schedule an appointment with a Nebraska Medicine cancer specialist, call 402.559.5600.

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Are immunotherapy and chemotherapy the same thing? How cancer treatments work - Nebraska Medicine

Bone Marrow Stem Cells Comments Off on Are immunotherapy and chemotherapy the same thing? How cancer treatments work – Nebraska Medicine | October 5th, 2022

BOSTON--(BUSINESS WIRE)--Gamida Cell Ltd. (Nasdaq: GMDA), the leader in the development of NAM-enabled cell therapies for patients with hematologic and solid cancers and other serious diseases, today announced the presentation of new long term follow-up data and health-related quality of life scores of patients treated with omidubicel at the Tenth Annual Meeting of the Society of Hematologic Oncology (SOHO), being held in Houston, Texas.

These data reinforce our commitment to advance transformational cell therapy research and underscore the potential of our NAM technology platform. Our lead stem cell therapy candidate, omidubicel, addresses the unmet need for patients with hematologic malignancies, demonstrated by the robust and growing body of encouraging clinical evidence, including the long-term follow up data and quality of life improvement, said Ronit Simantov, M.D., Chief Medical Officer of Gamida Cell. As we approach the PDUFA date of January 30, 2023, and upon potential FDA approval, we are prepared to execute our plan that ensures access to those patients who can benefit from omidubicel as quickly as possible.

The long-term, durable clinical benefit of omidubicel was observed at three years across a patient population that typically has a poor prognosis. A study titled, Multicenter Long-Term Follow Up of Allogeneic Hematopoietic Stem Cell Transplantation with Omidubicel: A Pooled Analysis of Five Prospective Clinical Trials, highlighted long-term follow-up of 105 patients transplanted with omidubicel between 2006-2020 (median follow-up of 22 months). The data demonstrated an overall survival and disease-free survival of 63% (95% CI, 53%-73%) and 56% (95% CI, 47%-67%) at three years, respectively, as well as durable long-term hematopoiesis and immune competence. Learn More

Overall well-being health-related quality of life scores for patients treated with omidubicel demonstrated clinical benefit compared to standard of care. A study titled, Health-Related Quality of Life Following Allogeneic Hematopoietic Stem Cell Transplantation with Omidubicel Versus Standard Umbilical Cord Blood featured an analysis of 108 patients that completed validated health-related quality of life (HRQL) surveys on screening and days 42, 100, 180, and 365 post-transplant. Measures of physical and functional well-being and other HRQL scores were more favorable with omidubicel. These data suggest clinically meaningful and sustained improvements in physical, functional, and overall well-being compared to umbilical cord blood transplantation. Learn More

About NAM Technology

Our NAM-enabling technology is designed to enhance the number and functionality of targeted cells, enabling us to pursue a curative approach that moves beyond what is possible with existing therapies. Leveraging the unique properties of NAM (nicotinamide), we can expand and metabolically modulate multiple cell types including stem cells and natural killer cells with appropriate growth factors to maintain the cells active phenotype and enhance potency. Additionally, our NAM technology improves the metabolic fitness of cells, allowing for continued activity throughout the expansion process.

About Omidubicel

Omidubicel is an advanced cell therapy candidate developed as a potential life-saving allogeneic hematopoietic stem cell (bone marrow) transplant for patients with blood cancers. Omidubicel demonstrated a statistically significant reduction in time to neutrophil engraftment in comparison to standard umbilical cord blood in an international, multi-center, randomized Phase 3 study (NCT0273029) in patients with hematologic malignancies undergoing allogeneic bone marrow transplant. The Phase 3 study also showed reduced time to platelet engraftment, reduced infections and fewer days of hospitalization. One-year post-transplant data showed sustained clinical benefits with omidubicel as demonstrated by significant reduction in infectious complications as well as reduced non-relapse mortality and no significant increase in relapse rates nor increases in graft-versus-host-disease (GvHD) rates. Omidubicel is the first stem cell transplant donor source to receive Breakthrough Therapy Designation from the FDA and has also received Orphan Drug Designation in the US and EU.

Omidubicel is an investigational stem cell therapy candidate, and its safety and efficacy have not been established by the FDA or any other health authority. For more information about omidubicel, please visit https://www.gamida-cell.com.

About Gamida Cell

Gamida Cell is pioneering a diverse immunotherapy pipeline of potentially curative cell therapy candidates for patients with solid tumor and blood cancers and other serious blood diseases. We apply a proprietary expansion platform leveraging the properties of NAM to allogeneic cell sources including umbilical cord blood-derived cells and NK cells to create therapy candidates with potential to redefine standards of care. These include omidubicel, an investigational product with potential as a life-saving alternative for patients in need of bone marrow transplant, and a line of modified and unmodified NAM-enabled NK cells targeted at solid tumor and hematological malignancies. For additional information, please visit http://www.gamida-cell.com or follow Gamida Cell on LinkedIn, Twitter, Facebook or Instagram at @GamidaCellTx.

Cautionary Note Regarding Forward Looking Statements

This press release contains forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995, including with respect to timing of initiation and progress of, and data reported from, the clinical trials of Gamida Cells product candidates (including omidubicel), regulatory filings submitted to the FDA (including the potential timing of the FDAs review of the BLA for omidubicel), commercialization planning efforts, and the potentially life-saving or curative therapeutic and commercial potential of Gamida Cells product candidates (including omidubicel), and Gamida Cells expectations for the expected clinical development milestones set forth herein. Any statement describing Gamida Cells goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to a number of risks, uncertainties and assumptions, including those related to the impact that the COVID-19 pandemic could have on our business, and including the scope, progress and expansion of Gamida Cells clinical trials and ramifications for the cost thereof; clinical, scientific, regulatory and technical developments; and those inherent in the process of developing and commercializing product candidates that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such product candidates. In light of these risks and uncertainties, and other risks and uncertainties that are described in the Risk Factors section and other sections of Gamida Cells Quarterly Report on Form 10-Q, filed with the Securities and Exchange Commission (SEC) on May 12, 2022, as amended, and other filings that Gamida Cell makes with the SEC from time to time (which are available at http://www.sec.gov), the events and circumstances discussed in such forward-looking statements may not occur, and Gamida Cells actual results could differ materially and adversely from those anticipated or implied thereby. Although Gamida Cells forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Gamida Cell. As a result, you are cautioned not to rely on these forward-looking statements.

1CIBMTR 2019 allogeneic transplants in patients 12+ years with hematological malignancies.2Gamida Cell market research

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Long-Term Data from Omidubicel Phase 3 Trial Demonstrates Overall Survival and Sustainable Durable Outcomes for Patients with Blood Cancers at the...

Bone Marrow Stem Cells Comments Off on Long-Term Data from Omidubicel Phase 3 Trial Demonstrates Overall Survival and Sustainable Durable Outcomes for Patients with Blood Cancers at the… | October 5th, 2022

Dr. Jeff Hersh| Daily News Correspondent

Q: What is CAR T-cell therapy?

A: Our immune system protects our bodies from "invasion"by harmful substances, infections and abnormal cells (for example cancer cells). T-cells (also called T-lymphocytes or thymocytes) develop from stem cells in the bone marrow and mature in the thymus (a body organ in the neck that is part of the lymphoid system, along with the spleen, lymph nodes and the red bone marrow).

Cytotoxic T-cells identify body cells that have certain antigens (proteins on the surface of certain cancer cells, cells that have become infected, other cells) and directly kill them.

Helper T-cells detect various "invasions"and release cytokines to activate other immune system cells (including cytotoxic T-cells) to combat them.

Regulatory T-cells help moderate the immune response to maintain balance and the bodys ability to tolerate (rather than attack) itself (for example helping minimize inappropriate inflammatory responses).

This description of T-cells shows why it would be helpful to "manipulate"them in a specific manner to leverage the immune system to help fight certain diseases/conditions. This is where chimeric antigen receptor (CAR) T-cells come into play.

White blood cells (including T-cells) are collected from the patient by taking some of their blood via an intravenous (IV) catheter and filtering out the white cells using a leukapheresis machine, and then putting the filtered blood (minus the extracted white blood cells) back into the patient via a second IV catheter.

The T-cells are then separated from the other white blood cells, and a gene for the "targeted" antigen is added to the cells (you can think of this as a "lock and key"mechanism, with the antigen being the "lock"and the protein added to the T-cell being the "key"used to identify the "invading" cell with that particular antigen "lock."

These modified cells (the CAR T-cells) are then "multiplied"in the lab to create a large number of them. The CAR T-cells are then infused into the patient (again via an IV). These CAR T-cells can now specifically "hunt"the specific "invading"cell(s) they have been created to target.

There are many steps needed to create this personalized CAR T-cell treatment for an individual patient, and therefore it can take weeks to produce these treatments. In the future it may be possible to pre-prepare treatments from donor T-cells (possibly modifying these cells to target specific antigens using techniques like CRISPR, mRNA techniques, etc.) and then transfuse the appropriate CAR T-cells in a manner similar to how other blood products (for example red cells, platelets, etc.) are transfused to help a patient.

Since 2017 CAR T-cells have been specifically designed and utilized to treat individual patients with several different types of "blood cancers"(lymphomas, leukemias and multiple myelomas) that did not respond to the standard treatments (for example chemotherapy for that type of cancer).In many patients with very difficult to treat blood cancers, these treatments have been very effective.

Solid tumors (as opposed to blood cancers), such as brain, breast, lung and pancreatic cancers, are a bit more challenging to address with the CAR T-cell approach.This is because having the CAR T-cells gain "access"to the solid tumor cancer cells is more difficult.

From the description of T-cells above, it seems that this same conceptual approach might be utilized to treat certain autoimmune conditions (conditions where a patients own immune system "overreacts"and attacks the patients own body cells), and this has recently been studied. In this study, five patients with severe lupus who had not responded to standard treatments were treated with specifically designed CAR T-cells to "wipe out"the aberrant B cells causing their autoimmune complications, and all five showed very significant improvement. Future clinical studies will no doubt be designed to see what other conditions might benefit from this treatment approach!

However, treatment with CAR T-cells is not without risk, as these treatments can sometimes cause serious and even life-threatening complications. For example, some patients have had:

Cytokine release syndrome (CRS), where the patient reacts to the CAR T-cell infusion with an aggressive release of cytokines that causes an inflammatory reaction (for example causing symptoms like fever, breathing issues, gastrointestinal issues, other symptoms); nervous system issues (for example headaches, seizures, alterations in consciousness, others), and there may bemany other possible complications.

Bottom line: CAR T-cell therapy has become a more and more accepted therapeutic approach, and in the future it may be utilized earlier in a patients disease (rather than only for refractory cases), and for a broader array of disease states (not just blood cancers, but potentially autoimmune conditions, maybe certain solid tumors, and potentially other diseases).

Jeff Hersh, Ph.D., M.D., can be reached at DrHersh@juno.com.

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CAR T-cell therapy is new approach to fighting cancer, other diseases - MetroWest Daily News

Bone Marrow Stem Cells Comments Off on CAR T-cell therapy is new approach to fighting cancer, other diseases – MetroWest Daily News | October 5th, 2022