EL PASO, Texas -- Biomedical research scientists from Texas Tech University Health Sciences Center El Paso and The University of Texas at El Paso are partnering up to send "artificial mini-hearts" to the International Space Station to better understand how microgravity affects the function of the human heart.

The three-year project, funded by the National Science Foundation (NSF) and the space station's U.S. National Laboratory, brings together TTUHSC El Paso faculty scientist Munmun Chattopadhyay, Ph.D., and UTEP biomedical engineer Binata Joddar, Ph.D. The researchers will collaborate in their Earth-bound labs to create tiny (less than 1 millimeter thick) heart-tissue structures, known as cardiac organoids, using human stem cells and 3D bioprinting technology.

By exposing the organoids to the near-weightless environment of the orbiting space station, the researchers hope to gain a better understanding of a health condition known as cardiac atrophy, which is a reduction and weakening of heart tissue. Cardiac atrophy often affects astronauts who spend long periods of time in microgravity. A weakened heart muscle has difficulty pumping blood to the body, and can lead to problems such as fainting, irregular heartbeat, heart valve problems and even heart failure. Cardiac atrophy is also associated with chronic disease.

The first year of the project, which began in September, will focus on research design. During this phase, Dr. Joddar will use 3D printing to fabricate the cardiac organoids by coupling cardiac cells in physiological ratios to mimic heart tissue. The second year will be centered on preparing the organoid payload for a rocket launch and mission in space. The third and final year of the research will involve analyzing data from the experiment after the organoids are returned to Earth.

The project will also provide an educational opportunity for the El Paso community, with a workshop for K-12 students to learn about tissue engineering projects on the space station. It will also include a seminar for medical students, interns and residents about the benefits and challenges of transitioning research from Earth-based laboratories into space.

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El Paso scientists team up for project that will be sent to the International Space Station - KVIA El Paso

Cardiac Stem Cells Comments Off on El Paso scientists team up for project that will be sent to the International Space Station – KVIA El Paso | January 23rd, 2020

Ncardia and BlueRock Therapeutics today announced an agreement covering process development technologies for the manufacture of induced pluripotent stem cell (iPSC)-derived cardiomyocytes. Under the terms of the agreement, Bluerock gains access to Ncardias large-scale production processes and intellectual property for the production of iPSC-derived cardiomyocytes for therapeutic use.

This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20200121005200/en/

"BlueRock is a leader in the field of cell therapy and our collaboration is a perfect match of mission and capabilities. This relationship allows us to utilize our experience in iPSC process development to help advance potential cell therapies for cardiac diseases," said Stefan Braam, CEO of Ncardia.

"There are hundreds of millions of people worldwide that suffer from degenerative cardiovascular disease where the root cause is the loss of healthy heart muscle cells, and where medical treatment options are limited. BlueRocks authentic cellular therapy is a novel approach that has the potential to transform the lives of patients, but will require the manufacture of our cell therapies at unprecedented scale. The Ncardia team has developed key technologies related to this scale-up challenge, and we are pleased to work with them as we advance BlueRocks novel CELL+GENE platform towards the clinic and those patients in need," said Emile Nuwaysir, President and CEO, BlueRock Therapeutics.

About BlueRock Therapeutics

BlueRock Therapeutics, a wholly owned and independently operated subsidiary of Bayer AG, is a leading engineered cell therapy company with a mission to develop regenerative medicines for intractable diseases. BlueRock Therapeutics CELL+GENE platform harnesses the power of cells for new medicines across neurology, cardiology and immunology indications. BlueRock Therapeutics cell differentiation technology recapitulates the cells developmental biology to produce authentic cell therapies, which are further engineered for additional function. Utilizing these cell therapies to replace damaged or degenerated tissue brings the potential to restore or regenerate lost function. BlueRocks culture is defined by scientific innovation, highest ethical standards and an urgency to bring transformative treatments to all who would benefit. For more information, visit http://www.bluerocktx.com.

About Ncardia

Ncardia believes that stem cell technology can deliver better therapies to patients faster. We bring cell manufacturing and process development expertise to cell therapy by designing and delivering human induced pluripotent stem cell (iPSC) solutions to specification. Our offerings extend from concept development to pre-clinical studies, including custom manufacturing of a range of cell types, as well as discovery services such as disease modelling, screening, and safety assays. For more information, visit http://www.ncardia.com.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200121005200/en/

Contacts

BlueRock:media@bluerocktx.com

Ncardia:Steven Dublinmedia@ncardia.com

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Ncardia and BlueRock Therapeutics Announce Collaboration Agreement and Licensing of Process Development Technologies for the Manufacture of...

Cardiac Stem Cells Comments Off on Ncardia and BlueRock Therapeutics Announce Collaboration Agreement and Licensing of Process Development Technologies for the Manufacture of… | January 22nd, 2020

Theres a team of scientists who basically discovered live robots. You read that right. They found a new purpose for living cells, which they took from frog embryos, and they constructed new life forms. These life forms were named Xenobots, and they can move in small places and carry stuff, too. They also want to try to see if they are useful in medicine.

Apparently, they can heal themselves after theyre cut, which gives them a longer life span. They are not a species of animals, and they are not robots in a real way. As Joshua Bongard states, Its a new class of artifact: a living, programmable organism. He is a computer scientist at the University of Vermont.

A supercomputer developed these live robots at UVM. The idea behind this creation is not a new one. But it is the first time they actually improved it from scratch. The team was led by doctoral student Sam Kriegman, who used an evolutionary algorithm to develop thousands of designs for these new life forms.

They gave the program the basic rules about biophysics about the frog skin and the cardiac cells. They tested about a hundred algorithms to find the best design. Then, the team worked with microsurgeons to transfer the silicon designs into life. They took the stem cells from Xenopus lavevis, an African frog. Then the embryos were assembled in body forms, so the cells began to work.

Almost everything we see today is made out of steel, silicon, or plastic. While its true that the material is durable, it also creates human health problems. Bongard stated that the living tissues degrade quickly. Also, these living robots made with frog cells could help us live a healthier life. More research will be conducted.

Tanya is an expert in reddit and health subjects. She finds good stories where no one ever thinks to look.

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The Living Robots Made With Frog Cells Could Boost Our Health - Dual Dove

Cardiac Stem Cells Comments Off on The Living Robots Made With Frog Cells Could Boost Our Health – Dual Dove | January 22nd, 2020

US Stem Cell (OTCMKTS:USRM) and National Research (NASDAQ:NRC) are both small-cap medical companies, but which is the superior investment? We will compare the two companies based on the strength of their earnings, risk, valuation, dividends, profitability, analyst recommendations and institutional ownership.

Institutional & Insider Ownership

39.7% of National Research shares are owned by institutional investors. 16.7% of US Stem Cell shares are owned by insiders. Comparatively, 4.5% of National Research shares are owned by insiders. Strong institutional ownership is an indication that hedge funds, endowments and large money managers believe a stock will outperform the market over the long term.

Analyst Recommendations

This is a breakdown of current ratings and price targets for US Stem Cell and National Research, as provided by MarketBeat.com.

Volatility & Risk

US Stem Cell has a beta of 4.87, meaning that its stock price is 387% more volatile than the S&P 500. Comparatively, National Research has a beta of 0.78, meaning that its stock price is 22% less volatile than the S&P 500.

Valuation and Earnings

This table compares US Stem Cell and National Researchs gross revenue, earnings per share (EPS) and valuation.

National Research has higher revenue and earnings than US Stem Cell.

Profitability

This table compares US Stem Cell and National Researchs net margins, return on equity and return on assets.

Summary

National Research beats US Stem Cell on 7 of the 9 factors compared between the two stocks.

US Stem Cell Company Profile

U.S. Stem Cell, Inc., a biotechnology company, focuses on the discovery, development, and commercialization of autologous cellular therapies for the treatment of chronic and acute heart damage, and vascular and autoimmune diseases in the United States and internationally. Its lead product candidates include MyoCell, a clinical therapy designed to populate regions of scar tissue within a patient's heart with autologous muscle cells or cells from a patient's body for enhancing cardiac function in chronic heart failure patients; and AdipoCell, a patient-derived cell therapy for the treatment of acute myocardial infarction, chronic heart ischemia, and lower limb ischemia. The company's product development pipeline includes MyoCell SDF-1, an autologous muscle-derived cellular therapy for improving cardiac function in chronic heart failure patients. It is also developing MyoCath, a deflecting tip needle injection catheter that is used to inject cells into cardiac tissue in therapeutic procedures to treat chronic heart ischemia and congestive heart failure. In addition, the company provides physician and patient based regenerative medicine/cell therapy training, cell collection, and cell storage services; and cell collection and treatment kits for humans and animals, as well operates a cell therapy clinic. The company was formerly known as Bioheart, Inc. and changed its name to U.S. Stem Cell, Inc. in October 2015. U.S. Stem Cell, Inc. was founded in 1999 and is headquartered in Sunrise, Florida.

National Research Company Profile

National Research Corporation (NRC) is a provider of analytics and insights that facilitate revenue growth, patient, employee and customer retention and patient engagement for healthcare providers, payers and other healthcare organizations. The Companys portfolio of subscription-based solutions provides information and analysis to healthcare organizations and payers across a range of mission-critical, constituent-related elements, including patient experience and satisfaction, community population health risks, workforce engagement, community perceptions, and physician engagement. The Companys clients range from acute care hospitals and post-acute providers, such as home health, long term care and hospice, to numerous payer organizations. The Company derives its revenue from its annually renewable services, which include performance measurement and improvement services, healthcare analytics and governance education services.

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National Research (NASDAQ:NRC) versus US Stem Cell (NASDAQ:USRM) Head-To-Head Review - Riverton Roll

Cardiac Stem Cells Comments Off on National Research (NASDAQ:NRC) versus US Stem Cell (NASDAQ:USRM) Head-To-Head Review – Riverton Roll | January 22nd, 2020

Transparency Market Research (TMR)has published a new report on the globalcell separation technology marketfor the forecast period of 20192027. According to the report, the global cell separation technology market was valued at ~US$ 5 Bnin 2018, and is projected to expand at a double-digit CAGR during the forecast period.

Overview

Cell separation, also known as cell sorting or cell isolation, is the process of removing cells from biological samples such as tissue or whole blood. Cell separation is a powerful technology that assists biological research. Rising incidences of chronic illnesses across the globe are likely to boost the development of regenerative medicines or tissue engineering, which further boosts the adoption of cell separation technologies by researchers.

Expansion of the global cell separation technology market is attributed to an increase in technological advancements and surge in investments in research & development, such asstem cellresearch and cancer research. The rising geriatric population is another factor boosting the need for cell separation technologies Moreover, the geriatric population, globally, is more prone to long-term neurological and other chronic illnesses, which, in turn, is driving research to develop treatment for chronic illnesses. Furthermore, increase in the awareness about innovative technologies, such as microfluidics, fluorescent-activated cells sorting, and magnetic activated cells sorting is expected to propel the global cell separation technology market.

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North America dominated the global cell separation technology market in 2018, and the trend is anticipated to continue during the forecast period. This is attributed to technological advancements in offering cell separation solutions, presence of key players, and increased initiatives by governments for advancing the cell separation process. However, insufficient funding for the development of cell separation technologies is likely to hamper the global cell separation technology market during the forecast period. Asia Pacific is expected to be a highly lucrative market for cell separation technology during the forecast period, owing to improving healthcare infrastructure along with rising investments in research & development in the region.

Rising Incidences of Chronic Diseases, Worldwide, Boosting the Demand for Cell Therapy

Incidences of chronic diseases such as diabetes, obesity, arthritis, cardiac diseases, and cancer are increasing due to sedentary lifestyles, aging population, and increased alcohol consumption and cigarette smoking. According to the World Health Organization (WHO), by 2020, the mortality rate from chronic diseases is expected to reach73%, and in developing counties,70%deaths are estimated to be caused by chronic diseases. Southeast Asia, Eastern Mediterranean, and Africa are expected to be greatly affected by chronic diseases. Thus, the increasing burden of chronic diseases around the world is fuelling the demand for cellular therapies to treat chronic diseases. This, in turn, is driving focus and investments on research to develop effective treatments. Thus, increase in cellular research activities is boosting the global cell separation technology market.

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Increase in Geriatric Population Boosting the Demand for Surgeries

The geriatric population is likely to suffer from chronic diseases such as cancer and neurological disorders more than the younger population. Moreover, the geriatric population is increasing at a rapid pace as compared to that of the younger population. Increase in the geriatric population aged above 65 years is projected to drive the incidences of Alzheimers, dementia, cancer, and immune diseases, which, in turn, is anticipated to boost the need for corrective treatment of these disorders. This is estimated to further drive the demand for clinical trials and research that require cell separation products. These factors are likely to boost the global cell separation technology market.

According to the United Nations, the geriatric population aged above 60 is expected to double by 2050 and triple by 2100, an increase from962 millionin 2017 to2.1 billionin 2050 and3.1 billionby 2100.

Productive Partnerships in Microfluidics Likely to Boost the Cell Separation Technology Market

Technological advancements are prompting companies to innovate in microfluidics cell separation technology. Strategic partnerships and collaborations is an ongoing trend, which is boosting the innovation and development of microfluidics-based products. Governments and stakeholders look upon the potential in single cell separation technology and its analysis, which drives them to invest in the development ofmicrofluidics. Companies are striving to build a platform by utilizing their expertise and experience to further offer enhanced solutions to end users.

Stem Cell Research to Account for a Prominent Share

Stem cell is a prominent cell therapy utilized in the development of regenerative medicine, which is employed in the replacement of tissues or organs, rather than treating them. Thus, stem cell accounted for a prominent share of the global market. The geriatric population is likely to increase at a rapid pace as compared to the adult population, by 2030, which is likely to attract the use of stem cell therapy for treatment. Stem cells require considerably higher number of clinical trials, which is likely to drive the demand for cell separation technology, globally. Rising stem cell research is likely to attract government and private funding, which, in turn, is estimated to offer significant opportunity for stem cell therapies.

Biotechnology & Pharmaceuticals Companies to Dominate the Market

The number of biotechnology companies operating across the globe is rising, especially in developing countries. Pharmaceutical companies are likely to use cells separation techniques to develop drugs and continue contributing through innovation. Growing research in stem cell has prompted companies to own large separate units to boost the same. Thus, advancements in developing drugs and treatments, such as CAR-T through cell separation technologies, are likely to drive the segment.

As per research, 449 public biotech companies operate in the U.S., which is expected to boost the biotechnology & pharmaceutical companies segment. In developing countries such as China, China Food and Drug Administration(CFDA) reforms pave the way for innovation to further boost biotechnology & pharmaceutical companies in the country.

Global Cell Separation Technology Market: Prominent Regions

North America to Dominate Global Market, While Asia Pacific to Offer Significant Opportunity

In terms of region, the global cell separation technology market has been segmented into five major regions: North America, Europe, Asia Pacific, Latin America, and the Middle East & Africa. North America dominated the global market in 2018, followed by Europe. North America accounted for a major share of the global cell separation technology market in 2018, owing to the development of cell separation advanced technologies, well-defined regulatory framework, and initiatives by governments in the region to further encourage the research industry. The U.S. is a major investor in stem cell research, which accelerates the development of regenerative medicines for the treatment of various long-term illnesses.

The cell separation technology market in Asia Pacific is projected to expand at a high CAGR from 2019 to 2027. This can be attributed to an increase in healthcare expenditure and large patient population, especially in countries such as India and China. Rising medical tourism in the region and technological advancements are likely to drive the cell separation technology market in the region.

Launching Innovative Products, and Acquisitions & Collaborations by Key Players Driving Global Cell Separation Technology Market

The global cell separation technology market is highly competitive in terms of number of players. Key players operating in the global cell separation technology market include Akadeum Life Sciences, STEMCELL Technologies, Inc., BD, Bio-Rad Laboratories, Inc., Miltenyi Biotech, 10X Genomics, Thermo Fisher Scientific, Inc., Zeiss, GE Healthcare Life Sciences, PerkinElmer, Inc., and QIAGEN.

These players have adopted various strategies such as expanding their product portfolios by launching new cell separation kits and devices, and participation in acquisitions, establishing strong distribution networks. Companies are expanding their geographic presence in order sustain in the global cell separation technology market. For instance, in May 2019, Akadeum Life Sciences launched seven new microbubble-based products at a conference. In July 2017, BD received the U.S. FDAs clearance for its BD FACS Lyric flow cytometer system, which is used in the diagnosis of immunological disorders.

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Cell Separation Technology Market to Receive Overwhelming Hike in Revenues by 2027 Dagoretti News - Dagoretti News

Cardiac Stem Cells Comments Off on Cell Separation Technology Market to Receive Overwhelming Hike in Revenues by 2027 Dagoretti News – Dagoretti News | January 20th, 2020

Global Exosome Therapeutic Marketreport identifies and analyses the emerging trends along with major drivers, challenges and opportunities in industry with analysis on Market trends, share, growth,demand, top vendors, Geographical Regions, types, applications. Exosome Therapeutic industry report gives a comprehensive account of the Global Exosome Therapeutic market. Details such as the size, key players, segmentation, SWOT analysis, most influential trends, and business environment of the market are mentioned in this report.

Exosome Therapeutic Marketis expected to gain market growth in the forecast period of 2019 to 2026. Data Bridge Market Research analyses that the market is growing with a CAGR of 21.9% in the forecast period of 2019 to 2026 and expected to reach USD 31,691.52 million by 2026 from USD 6,500.00 million in 2018. Increasing prevalence of lyme disease, chronic inflammation, autoimmune disease and other chronic degenerative diseases are the factors for the market growth.

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Synopsis of Global Exosome Therapeutic Market:-Exosomes is used to transfer RNA, DNA, and proteins to other cells in the body by making alteration in the function of the target cells. Increasing research activities in exosome therapeutic is augmenting the market growth as demand for exosome therapeutic has increased among healthcare professionals.

Increased number of exosome therapeutics as compared to the past few years will accelerate the market growth. Companies are receiving funding for exosome therapeutic research and clinical trials. For instance, In September 2018, EXOCOBIO has raised USD 27 million in its series B funding. The company has raised USD 46 million as series a funding in April 2017. The series B funding will help the company to set up GMP-compliant exosome industrial facilities to enhance production of exosomes to commercialize in cosmetics and pharmaceutical industry.

Some Of The Major Competitors Currently Working In Global Exosome Therapeutic Market Are:Bayer AG, Iso-Tex Diagnostics, Inc., Bracco Diagnostic Inc., Novalek Pharmaceuticals Pvt. Ltd., iMAX, Taejoon Pharm, Unijules Medicals Ltd, General Electric, Guerbet LLC, J.B.Chemicals & Pharmaceuticals Ltd among others players domestic and global. DBMR analysts understand competitive strengths and provide competitive analysis for each competitor separately.

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North America Dominates The Exosome Therapeutic Market as the U.S. Is leaderin exosome therapeutic manufacturing as well as research activities required for exosome therapeutics. At present time Stem Cells Group holding shares around 60.00%. In addition global exosomes therapeutics manufacturers like EXOCOBIO, evox THERAPEUTICS and others are intensifying their efforts in China. The Europe region is expected to grow with the highest growth rate in the forecast period of 2019 to 2026 because of increasing research activities in exosome therapeutic by population.

Huge Investment by Automakers for Exosome Therapeutics and New Technology Penetration

Global exosome therapeutic market also provides you with detailed market analysis for every country growth in pharma industry with exosome therapeutic sales, impact of technological development in exosome therapeutic and changes in regulatory scenarios with their support for the exosome therapeutic market. The data is available for historic period 2010 to 2017.

Browse in-depth TOC on Exosome Therapeutic Market

50 Tables

250 No of Figures

150 Pages

This Exosome Therapeutic Market report contains all aspects that are directly or indirectly related to the multiple areas of the global market. Our experts have carefully collated the global Exosome Therapeutic Market data and estimated the change in the forecast period. This information in the report helps customers make accurate decisions about market activity Exosome Therapeutic Market based on forecasting trends. This report also discusses current or future policy research or regulations that must be initiated by management and market strategies.

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Global Exosome Therapeutic Market Scope and Market Size

Global Exosome Therapeutic Market is segmented of the basis of type, source, therapy, transporting capacity, application, route of administration and end user. The growth among segments helps you analyse niche pockets of growth and strategies to approach the market and determine your core application areas and the difference in your target markets.

Based on type, the market is segmented into natural exosomes and hybrid exosomes. Natural exosomes are dominating in the market because natural exosomes are used in various biological and pathological processes as well as natural exosomes has many advantages such as good biocompatibility and reduced clearance rate compare than hybrid exosomes.

Based on therapy, the market is segmented into immunotherapy, gene therapy and chemotherapy. Chemotherapy is dominating in the market because chemotherapy is basically used in treatment of cancer which is major public health issues. The multidrug resistance (MDR) proteins and various tumors associated exosomes such as miRNA and IncRNA are include in in chemotherapy associated resistance.

Based on transporting capacity, the market is segmented into bio macromolecules and small molecules. Bio macromolecules are dominating in the market because bio macromolecules transmit particular biomolecular information and are basically investigated for their delicate properties such as biomarker source and delivery system

Based on application, the market is segmented into oncology, neurology, metabolic disorders, cardiac disorders, blood disorders, inflammatory disorders, gynecology disorders, organ transplantation and others. Oncology segment is dominating in the market due to rising incidence of various cancers such as lung cancer, breast cancer, leukemia, skin cancer, lymphoma. As per the National Cancer Institute, in 2018 around 1,735,350 new cases of cancer was diagnosed in the U.S. As per the American Cancer Society Inc in 2019 approximately 268,600 new cases of breast cancer diagnosed in the U.S.To be continued..Detailed Segmentation ofExosome Therapeutic Market

The Countries Covered In The Exosome Therapeutic Market Report Are U.S., Canada and Mexico in North America, Germany, France, U.K., Netherlands, Switzerland, Belgium, Russia, Italy, Spain, Turkey, Rest of Europe in Europe, China, Japan, India, South Korea, Singapore, Malaysia, Australia, Thailand, Indonesia, Philippines, Rest of Asia-Pacific in the Asia-Pacific, South Africa, Rest of Middle East and Africa as a part of Middle East and Africa, Brazil and Rest of South America as part of South America.

Along with the elaborated information about the key contenders, the globalExosome Therapeutic Marketreport efficiently provides information by segmenting the market on the basis of the type services and products offerings, form of the product, applications of the final products, technology on which the product is based, and others. The report is also bifurcated the market on the basis of regions to analyze the growth pattern of the market in different geographical areas.

The Exosome Therapeutic Market report includes the leading advancements and technological up-gradation that engages the user to inhabit with fine business selections, define their future-based priority growth plans, and to implement the necessary actions. The global Exosome Therapeutic Market report also offers a detailed summary of key players and their manufacturing procedure with statistical data and profound analysis of the products, contribution, and revenue.

Global Exosome Therapeutic Market Report includes Detailed TOC points:

1 Introduction

2Market Segmentation

3 Market Overview

3.3 Opportunities

4 Executive Summaries

5 Premium Insights

6 Regulatory Procedure

7 Global Exosome Therapeutic Market, By Type

8 Global Exosome Therapeutic Market, by disease type

9 Global Exosome Therapeutic Market, By Deployment

10 Global Exosome Therapeutic Market, By End User

11 Global Exosome Therapeutic Market, By Distribution Channel

12 Global Exosome Therapeutic Market, By Geography

13 Global Exosome Therapeutic Market, Company Landscape

14 Company Profile

Continued!!!

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Exosome Therapeutic Market 2020 Modest Situation among the Top Manufacturers, With Sales, Revenue and Market Share 2026 Dagoretti News - Dagoretti...

Cardiac Stem Cells Comments Off on Exosome Therapeutic Market 2020 Modest Situation among the Top Manufacturers, With Sales, Revenue and Market Share 2026 Dagoretti News – Dagoretti… | January 20th, 2020

The following are the top rated Healthcare stocks according to Validea's Small-Cap Growth Investor model based on the published strategy of Motley Fool. This strategy looks for small cap growth stocks with solid fundamentals and strong price performance.

ZYNEX INC. (ZYXI) is a small-cap growth stock in the Medical Equipment & Supplies industry. The rating according to our strategy based on Motley Fool is 83% based on the firms underlying fundamentals and the stocks valuation. A score of 80% or above typically indicates that the strategy has some interest in the stock and a score above 90% typically indicates strong interest.

Company Description: Zynex, Inc. operates through the Electrotherapy and Pain Management Products segment. The Company conducts its business through its subsidiaries and the operating subsidiary is Zynex Medical, Inc. (ZMI). Its other subsidiaries include Zynex Monitoring Solutions, Inc. (ZMS) and Zynex Europe, ApS (ZEU). ZMI designs, manufactures and markets medical devices that treat chronic and acute pain, as well as activate and exercise muscles for rehabilitative purposes with electrical stimulation. ZMS is in the process of developing its blood volume monitoring product for non-invasive cardiac monitoring. ZEU intends to focus on sales and marketing its products within the international marketplace, upon receipt of necessary regulatory approvals. It markets and sells Zynex-manufactured products and distributes private labeled products. Its products include NexWave, NeuroMove, InWave, Electrodes and Batteries. ZMI devices are intended for pain management to reduce reliance on drugs and medications.

The following table summarizes whether the stock meets each of this strategy's tests. Not all criteria in the below table receive equal weighting or are independent, but the table provides a brief overview of the strong and weak points of the security in the context of the strategy's criteria.

For a full detailed analysis using NASDAQ's Guru Analysis tool, click here

LEMAITRE VASCULAR INC (LMAT) is a small-cap growth stock in the Medical Equipment & Supplies industry. The rating according to our strategy based on Motley Fool is 80% based on the firms underlying fundamentals and the stocks valuation. A score of 80% or above typically indicates that the strategy has some interest in the stock and a score above 90% typically indicates strong interest.

Company Description: LeMaitre Vascular, Inc. is a provider of medical devices for the treatment of peripheral vascular disease. The Company develops, manufactures and markets medical devices and implants used primarily in the field of vascular surgery. It is engaged in the design, marketing, sales and technical support of medical devices and implants for the treatment of peripheral vascular disease industry segment. The Company's product lines include valvulotomes, balloon catheters, carotid shunts, biologic vascular patches, radiopaque marking tape, anastomotic clips, remote endarterectomy devices, laparoscopic cholecystectomy devices, prosthetic vascular grafts, biologic vascular grafts and powered phlebectomy devices. Its portfolio of peripheral vascular devices consists of brand name products that are used in arteries and veins outside of the heart, including the Expandable LeMaitre Valvulotome, the Pruitt F3 Carotid Shunt, VascuTape Radiopaque Tape and the XenoSure biologic patch.

The following table summarizes whether the stock meets each of this strategy's tests. Not all criteria in the below table receive equal weighting or are independent, but the table provides a brief overview of the strong and weak points of the security in the context of the strategy's criteria.

For a full detailed analysis using NASDAQ's Guru Analysis tool, click here

INMODE LTD (INMD) is a small-cap growth stock in the Medical Equipment & Supplies industry. The rating according to our strategy based on Motley Fool is 79% based on the firms underlying fundamentals and the stocks valuation. A score of 80% or above typically indicates that the strategy has some interest in the stock and a score above 90% typically indicates strong interest.

Company Description: Inmode Ltd is an Israel-based company. It designs, develops, manufactures and commercializes energy-based, minimally-invasive surgical aesthetic and medical treatment solutions. The Company's proprietary technologies are used by physicians to remodel subdermal adipose, or fatty, tissue in a variety of procedures including fat reduction with simultaneous skin tightening, face and body contouring and ablative skin rejuvenation treatments. Its products target a wide array of procedures including simultaneous fat killing and skin tightening, permanent hair reduction, skin appearance and texture, among others. The Company's products may be used on a variety of body parts, including the face, neck, abdomen, upper arms, thighs and intimate feminine regions. It owns six product platforms: BodyTite, Optimas, Votiva, Contoura, Triton and EmbraceRF. All are market and sell traditionally to plastic and facial surgeons, aesthetic surgeons and dermatologists, among others.

The following table summarizes whether the stock meets each of this strategy's tests. Not all criteria in the below table receive equal weighting or are independent, but the table provides a brief overview of the strong and weak points of the security in the context of the strategy's criteria.

For a full detailed analysis using NASDAQ's Guru Analysis tool, click here

BIOLIFE SOLUTIONS INC (BLFS) is a small-cap growth stock in the Medical Equipment & Supplies industry. The rating according to our strategy based on Motley Fool is 76% based on the firms underlying fundamentals and the stocks valuation. A score of 80% or above typically indicates that the strategy has some interest in the stock and a score above 90% typically indicates strong interest.

Company Description: BioLife Solutions, Inc. (BioLife) is engaged in the developing, manufacturing and marketing a portfolio of biopreservation tools and services for cells, tissues and organs, including clinical grade cell and tissue hypothermic storage and cryopreservation freeze media and a related cloud hosted biologistics cold chain management application for shippers. The Company's product offerings include hypothermic storage and cryopreservation freeze media products for cells, tissues, and organs; generic blood stem cell freezing and cell thawing media products; custom product formulation and custom packaging services; cold chain logistics services incorporating precision thermal packaging products and cloud-hosted Web applications, and contract aseptic manufacturing formulation, fill and finish services of liquid media products. Its products include HypoThermosol FRS, CryoStor, BloodStor, Cell Thawing Media, PrepaStor and biologistex cold-chain management service.

The following table summarizes whether the stock meets each of this strategy's tests. Not all criteria in the below table receive equal weighting or are independent, but the table provides a brief overview of the strong and weak points of the security in the context of the strategy's criteria.

For a full detailed analysis using NASDAQ's Guru Analysis tool, click here

MEDPACE HOLDINGS INC (MEDP) is a mid-cap growth stock in the Biotechnology & Drugs industry. The rating according to our strategy based on Motley Fool is 76% based on the firms underlying fundamentals and the stocks valuation. A score of 80% or above typically indicates that the strategy has some interest in the stock and a score above 90% typically indicates strong interest.

Company Description: Medpace Holdings, Inc. is a clinical contract research organization. The Company provides clinical research-based drug and medical device development services. The Company partners with pharmaceutical, biotechnology, and medical device companies in the development and execution of clinical trials. The Company's drug development services focus on full service Phase I-IV clinical development services and include development plan design, coordinated central laboratory, project management, regulatory affairs, clinical monitoring, data management and analysis, pharmacovigilance new drug application submissions, and post-marketing clinical support. The Company also provides bio-analytical laboratory services, clinical human pharmacology, imaging services, and electrocardiography reading support for clinical trials. The Company's operations are principally based in North America, Europe, and Asia.

The following table summarizes whether the stock meets each of this strategy's tests. Not all criteria in the below table receive equal weighting or are independent, but the table provides a brief overview of the strong and weak points of the security in the context of the strategy's criteria.

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Since its inception, Validea's strategy based on Motley Fool has returned 639.27% vs. 234.94% for the S&P 500. For more details on this strategy, click here

About Motley Fool: Brothers David and Tom Gardner often wear funny hats in public appearances, but they're hardly fools -- at least not the kind whose advice you should readily dismiss. The Gardners are the founders of the popular Motley Fool web site, which offers frank and often irreverent commentary on investing, the stock market, and personal finance. The Gardners' "Fool" really is a multi-media endeavor, offering not only its web content but also several books written by the brothers, a weekly syndicated newspaper column, and subscription newsletter services.

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Validea's Top Five Healthcare Stocks Based On Motley Fool - 1/19/2020 - Nasdaq

Cardiac Stem Cells Comments Off on Validea’s Top Five Healthcare Stocks Based On Motley Fool – 1/19/2020 – Nasdaq | January 20th, 2020

US Stem Cell (OTCMKTS:USRM) and National Research (NASDAQ:NRC) are both small-cap medical companies, but which is the better stock? We will compare the two businesses based on the strength of their earnings, dividends, analyst recommendations, valuation, profitability, risk and institutional ownership.

Insider and Institutional Ownership

39.7% of National Research shares are held by institutional investors. 16.7% of US Stem Cell shares are held by company insiders. Comparatively, 4.5% of National Research shares are held by company insiders. Strong institutional ownership is an indication that large money managers, hedge funds and endowments believe a company will outperform the market over the long term.

This table compares US Stem Cell and National Researchs net margins, return on equity and return on assets.

Valuation & Earnings

This table compares US Stem Cell and National Researchs top-line revenue, earnings per share (EPS) and valuation.

National Research has higher revenue and earnings than US Stem Cell.

Risk and Volatility

US Stem Cell has a beta of 4.87, suggesting that its share price is 387% more volatile than the S&P 500. Comparatively, National Research has a beta of 0.78, suggesting that its share price is 22% less volatile than the S&P 500.

Analyst Recommendations

This is a summary of recent ratings and recommmendations for US Stem Cell and National Research, as provided by MarketBeat.

Summary

National Research beats US Stem Cell on 7 of the 9 factors compared between the two stocks.

US Stem Cell Company Profile

U.S. Stem Cell, Inc., a biotechnology company, focuses on the discovery, development, and commercialization of autologous cellular therapies for the treatment of chronic and acute heart damage, and vascular and autoimmune diseases in the United States and internationally. Its lead product candidates include MyoCell, a clinical therapy designed to populate regions of scar tissue within a patient's heart with autologous muscle cells or cells from a patient's body for enhancing cardiac function in chronic heart failure patients; and AdipoCell, a patient-derived cell therapy for the treatment of acute myocardial infarction, chronic heart ischemia, and lower limb ischemia. The company's product development pipeline includes MyoCell SDF-1, an autologous muscle-derived cellular therapy for improving cardiac function in chronic heart failure patients. It is also developing MyoCath, a deflecting tip needle injection catheter that is used to inject cells into cardiac tissue in therapeutic procedures to treat chronic heart ischemia and congestive heart failure. In addition, the company provides physician and patient based regenerative medicine/cell therapy training, cell collection, and cell storage services; and cell collection and treatment kits for humans and animals, as well operates a cell therapy clinic. The company was formerly known as Bioheart, Inc. and changed its name to U.S. Stem Cell, Inc. in October 2015. U.S. Stem Cell, Inc. was founded in 1999 and is headquartered in Sunrise, Florida.

National Research Company Profile

National Research Corporation (NRC) is a provider of analytics and insights that facilitate revenue growth, patient, employee and customer retention and patient engagement for healthcare providers, payers and other healthcare organizations. The Companys portfolio of subscription-based solutions provides information and analysis to healthcare organizations and payers across a range of mission-critical, constituent-related elements, including patient experience and satisfaction, community population health risks, workforce engagement, community perceptions, and physician engagement. The Companys clients range from acute care hospitals and post-acute providers, such as home health, long term care and hospice, to numerous payer organizations. The Company derives its revenue from its annually renewable services, which include performance measurement and improvement services, healthcare analytics and governance education services.

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US Stem Cell (OTCMKTS:USRM) and National Research (OTCMKTS:NRC) Head to Head Review - Slater Sentinel

Cardiac Stem Cells Comments Off on US Stem Cell (OTCMKTS:USRM) and National Research (OTCMKTS:NRC) Head to Head Review – Slater Sentinel | January 17th, 2020

Remember Black Mirrors Metalhead episode where a robot dog shoots the protagonist with trackers in the face? The thought of having unwanted foreign intruders attacking us from inside was absolutely nightmarish. We might have something similar now, as scientists strive to innovate to create new and novel micro-robots every day, but, with scientific and sane intentions.

Now, researchers at the University of Vermont and Tufts University have created living robots out of actual healthy frog cells that have the potential to navigate through one's bloodstream and scrape out plaque from arteries. These robots, called xenobots, are essentially a bioengineering product made by harvesting skin, pumping heart cells from frogs, and clumping them with stem cells from its embryo. Whats more? They are fully biodegradable and self-healing!

According to a press release, scientists first used a supercomputer to design the new life-form that can move in a direction. After having created a biological model of the supercomputers vision, they assembled the clusters with the beating cardiac cells on one end acting as a pump to propel the clump forward through the water.

Using this technique, the team created a number of the living robots and watched as they were able to successfully push other objects around. The researchers also experimented with creating a pouch inside the new life-forms, allowing them to carry a payload around. Despite of having a very low motility, these robots can perform task that other machines cant do, like searching out nasty compounds or radioactive contamination, gathering microplastic in the oceans and so on. And while they may not be as strong as metals, theyre regenerative.

The notion of having living organisms inside our body, that can possibly be programmed for malicious intent, is nerve-wracking. With xenobots, scientists wish to resolve this fear and work on tackling the unintended consequences. A paper detailing the research was published in the Proceedings of the National Academy of Sciences.

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Scientists Turn Frog Cells Into Tiny Living Robots That Can Swim Through Your Body! - Mashable India

Cardiac Stem Cells Comments Off on Scientists Turn Frog Cells Into Tiny Living Robots That Can Swim Through Your Body! – Mashable India | January 17th, 2020

Scientists from the University of Vermont (UVM) and Tufts University in Massachusetts said on January 13, 2020, that theyve now assembled living cells into entirely new life-forms. They call them living robots, or xenobots for the frog species from whose cells the little robots sprang. The scientists describe them as tiny blobs, submillimeter in size (a millimeter is about 1/25th of an inch, so these little blobs are smaller than that). The blobs contain between 500 and 1,000 cells. They can heal themselves after being cut. The blobs have been able to scoot across a petri dish, self-organize, and even transport minute payloads. Maybe, eventually, theyll be able to carry a medicine to a specific place inside a human body, scrape plaque from arteries, search out radioactive contamination, or gather plastic pollution in Earths oceans.

And, yes, the scientists do acknowledge possible ethical issues. More about that below.

Joshua Bongard, a computer scientist and robotics expert at the University of Vermont who co-led the new research, said in a statement:

These are novel living machines. Theyre neither a traditional robot nor a known species of animal. Its a new class of artifact: a living, programmable organism

You look at the cells weve been building our xenobots with, and, genomically, theyre frogs. Its 100% frog DNA but these are not frogs. Then you ask, well, what else are these cells capable of building?

The results of the new research were published January 13 in the Proceedings of the National Academy of Sciences.

EarthSky 2020 lunar calendars are available! Only a few left. Order now!

A manufactured quadruped (4-footed) organism, 650-750 microns in diameter (a micron is a millionth of a meter). The scientists described this creature (if we can call it a creature) as a bit smaller than a pinhead. Image via Douglas Blackiston/ Tufts University/ University of Vermont.

In their published paper, these scientists wrote:

Most technologies are made from steel, concrete, chemicals, and plastics, which degrade over time and can produce harmful ecological and health side effects. It would thus be useful to build technologies using self-renewing and biocompatible materials, of which the ideal candidates are living systems themselves. Thus, we here present a method that designs completely biological machines from the ground up: computers automatically design new machines in simulation, and the best designs are then built by combining together different biological tissues. This suggests others may use this approach to design a variety of living machines to safely deliver drugs inside the human body, help with environmental remediation, or further broaden our understanding of the diverse forms and functions life may adopt.

The new creatures were designed on a supercomputer at UVM, and then assembled and tested by biologists at Tufts University. The scientists statement described their process this way:

With months of processing time on the Deep Green supercomputer cluster at UVMs Vermont Advanced Computing Core, the team including lead author and doctoral student Sam Kriegman of UVM [@Kriegmerica on Twitter] used an evolutionary algorithm to create thousands of candidate designs for the new life-forms. Attempting to achieve a task assigned by the scientists like locomotion in one direction the computer would, over and over, reassemble a few hundred simulated cells into myriad forms and body shapes. As the programs ran driven by basic rules about the biophysics of what single frog skin and cardiac cells can do the more successful simulated organisms were kept and refined, while failed designs were tossed out. After a hundred independent runs of the algorithm, the most promising designs were selected for testing.

Then the team at Tufts, led by Michael Levin and with key work by microsurgeon Douglas Blackiston transferred the in-silico designs into life. First they gathered stem cells, harvested from embryos of African frogs, the species Xenopus laevis [African clawed frogs; hence the name xenobots.]

These were separated into single cells and left to incubate. Then, using tiny forceps and an even tinier electrode, the cells were cut and joined under a microscope into a close approximation of the designs specified by the computer.

Assembled into body forms never seen in nature, the cells began to work together. The skin cells formed a more passive architecture, while the once-random contractions of heart muscle cells were put to work creating ordered forward motion as guided by the computers design, and aided by spontaneous self-organizing patterns allowing the robots to move on their own.

These reconfigurable organisms were shown to be able move in a coherent fashion and explore their watery environment for days or weeks, powered by embryonic energy stores. Turned over, however, they failed, like beetles flipped on their backs.

Later tests showed that groups of xenobots would move around in circles, pushing pellets into a central location spontaneously and collectively. Others were built with a hole through the center to reduce drag. In simulated versions of these, the scientists were able to repurpose this hole as a pouch to successfully carry an object.

Wow yes?

The scientists said they see this work as part of a bigger picture. And they acknowledged that some may fear the implications of rapid technological change and complex biological manipulations. Levin commented:

That fear is not unreasonable. When we start to mess around with complex systems that we dont understand, were going to get unintended consequences.

However, he said:

If humanity is going to survive into the future, we need to better understand how complex properties, somehow, emerge from simple rules.

He said much of science is focused on:

controlling the low-level rules. We also need to understand the high-level rules.

I think its an absolute necessity for society going forward to get a better handle on systems where the outcome is very complex. A first step towards doing that is to explore: how do living systems decide what an overall behavior should be and how do we manipulate the pieces to get the behaviors we want?

In other words, he said:

this study is a direct contribution to getting a handle on what people are afraid of, which is unintended consequences.

Bongard added:

Theres all of this innate creativity in life. We want to understand that more deeply and how we can direct and push it toward new forms.

On the left, the anatomical blueprint for a computer-designed organism, discovered on a UVM supercomputer. On the right, the living organism, built entirely from frog skin (green) and heart muscle (red) cells. The background displays traces carved by a swarm of these new-to-nature organisms as they move through a field of particulate matter. Image via Sam Kriegman/ UVM.

Bottom line: Scientists said in early January 2020 that theyve created the first living robots, or xenobots, assembled from the cells of frogs. Their creators promise advances from drug delivery to toxic waste clean-up.

Source: A scalable pipeline for designing reconfigurable organisms

Via UVM

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Team builds the 1st living robots - EarthSky

Cardiac Stem Cells Comments Off on Team builds the 1st living robots – EarthSky | January 17th, 2020

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Autologous Stem Cell Based Therapies Market Report Analysis, Share, Revenue, Growth Rate With Forecast Overview To 2024 - Fusion Science Academy

Cardiac Stem Cells Comments Off on Autologous Stem Cell Based Therapies Market Report Analysis, Share, Revenue, Growth Rate With Forecast Overview To 2024 – Fusion Science Academy | January 17th, 2020

14 January 2020

These millimetre-wide "xenobots" can move toward a target, perhaps pick up a payload (like a medicine that needs to be carried to a specific place inside a patient) and heal themselves after being cut.

"These are novel living machines," says Joshua Bongard, a computer scientist and robotics expert at the University of Vermont who co-led the new research. "They're neither a traditional robot nor a known species of animal. It's a new class of artefact: a living, programmable organism."

The new creatures were designed on a supercomputer at UVM and then assembled and tested by biologists at Tufts University. "We can imagine many useful applications of these living robots that other machines can't do," says co-leader Michael Levin who directs the Centre for Regenerative and Developmental Biology at Tufts, "like searching out nasty compounds or radioactive contamination, gathering microplastic in the oceans, traveling in arteries to scrape out plaque."

The results of the new research were published January 13 in the Proceedings of the National Academy of Sciences.

Bespoke living systems

People have been manipulating organisms for human benefit since at least the dawn of agriculture, genetic editing is becoming widespread, and a few artificial organisms have been manually assembled in the past few years copying the body forms of known animals.

But this research, for the first time ever, "designs completely biological machines from the ground up," the team writes in their new study.

With months of processing time on the Deep Green supercomputer cluster at UVM's Vermont Advanced Computing Core, the team including lead author and doctoral student Sam Kriegman used an evolutionary algorithm to create thousands of candidate designs for the new life-forms. Attempting to achieve a task assigned by the scientists like locomotion in one direction the computer would, over and over, reassemble a few hundred simulated cells into myriad forms and body shapes. As the programs ran driven by basic rules about the biophysics of what single frog skin and cardiac cells can do the more successful simulated organisms were kept and refined, while failed designs were tossed out. After a hundred independent runs of the algorithm, the most promising designs were selected for testing.

Then the team at Tufts, led by Levin and with key work by microsurgeon Douglas Blackiston, transferred the in-silico designs into life. First, they gathered stem cells, harvested from the embryos of African frogs, the species Xenopus laevis. (Hence the name "xenobots.") These were separated into single cells and left to incubate. Then, using tiny forceps and an even tinier electrode, the cells were cut and joined under a microscope into a close approximation of the designs specified by the computer.

Assembled into body forms never seen in nature, the cells began to work together. The skin cells formed a more passive architecture, while the once-random contractions of heart muscle cells were put to work creating ordered forward motion as guided by the computer's design and aided by spontaneous self-organising patterns allowing the robots to move on their own.

These reconfigurable organisms were shown to be able move in a coherent fashion and explore their watery environment for days or weeks, powered by embryonic energy stores. Turned over, however, they failed, like beetles flipped on their backs.

Later tests showed that groups of xenobots would move around in circles, pushing pellets into a central location spontaneously and collectively. Others were built with a hole through the centre to reduce drag. In simulated versions of these, the scientists were able to repurpose this hole as a pouch to successfully carry an object. "It's a step toward using computer-designed organisms for intelligent drug delivery," says Bongard, a professor in UVM's Department of Computer Science and Complex Systems Centre.

Living technologies

Many technologies are made of steel, concrete or plastic. That can make them strong or flexible. But they also can create ecological and human health problems, like the growing scourge of plastic pollution in the oceans and the toxicity of many synthetic materials and electronics. "The downside of living tissue is that it's weak and it degrades," says Bongard. "That's why we use steel. But organisms have 4.5 billion years of practice at regenerating themselves and going on for decades." And when they stop working death they usually fall apart harmlessly. "These xenobots are fully biodegradable," say Bongard, "when they're done with their job after seven days, they're just dead skin cells."

Your laptop is a powerful technology. But try cutting it in half. Doesn't work so well. In the new experiments, the scientists cut the xenobots and watched what happened. "We sliced the robot almost in half and it stitches itself back up and keeps going," says Bongard. "And this is something you can't do with typical machines."

Cracking the Code

Both Levin and Bongard say the potential of what they've been learning about how cells communicate and connect extends deep into both computational science and our understanding of life. "The big question in biology is to understand the algorithms that determine form and function," says Levin. "The genome encodes proteins, but transformative applications await our discovery of how that hardware enables cells to cooperate toward making functional anatomies under very different conditions."

To make an organism develop and function, there is a lot of information sharing and cooperation organic computation going on in and between cells all the time, not just within neurons. These emergent and geometric properties are shaped by bioelectric, biochemical, and biomechanical processes, "that run on DNA-specified hardware," Levin says, "and these processes are reconfigurable, enabling novel living forms."

The scientists see the work presented in their new PNAS study "A scalable pipeline for designing reconfigurable organisms," as one step in applying insights about this bioelectric code to both biology and computer science. "What actually determines the anatomy towards which cells cooperate?" Levin asks. "You look at the cells we've been building our xenobots with, and, genomically, they're frogs. It's 100% frog DNA but these are not frogs. Then you ask, well, what else are these cells capable of building?"

"As we've shown, these frog cells can be coaxed to make interesting living forms that are completely different from what their default anatomy would be," says Levin. He and the other scientists in the UVM and Tufts team with support from DARPA's Lifelong Learning Machines program and the National Science Foundation believe that building the xenobots is a small step toward cracking what he calls the "morphogenetic code," providing a deeper view of the overall way organisms are organised and how they compute and store information based on their histories and environment.

Many people worry about the implications of rapid technological change and complex biological manipulations. "That fear is not unreasonable," Levin says. "When we start to mess around with complex systems that we don't understand, we're going to get unintended consequences." A lot of complex systems, like an ant colony, begin with a simple unit an ant from which it would be impossible to predict the shape of their colony or how they can build bridges over water with their interlinked bodies.

"If humanity is going to survive into the future, we need to better understand how complex properties, somehow, emerge from simple rules," says Levin. Much of science is focused on "controlling the low-level rules. We also need to understand the high-level rules," he says. "If you wanted an anthill with two chimneys instead of one, how do you modify the ants? We'd have no idea."

"I think it's an absolute necessity for society going forward to get a better handle on systems where the outcome is very complex," Levin says. "A first step towards doing that is to explore: how do living systems decide what an overall behaviour should be and how do we manipulate the pieces to get the behaviours we want?"

In other words, "this study is a direct contribution to getting a handle on what people are afraid of, which is unintended consequences," Levin says whether in the rapid arrival of self-driving cars, changing gene drives to wipe out whole lineages of viruses, or the many other complex and autonomous systems that will increasingly shape the human experience.

"There's all of this innate creativity in life," says UVM's Josh Bongard. "We want to understand that more deeply and how we can direct and push it toward new forms."

Information courtesy of University of Vermont

Excerpt from:
- Team builds first living robots using frog cells - Design Products & Applications

Cardiac Stem Cells Comments Off on – Team builds first living robots using frog cells – Design Products & Applications | January 17th, 2020

Forget gleaming metal droids -- the robots of the future may have more in common with the average amphibian than with R2D2.

A team of scientists have found a way to not just program a living organism, but to build brand new life-forms from scratch using cells, creating what researchers are calling xenobots.

Tiny in size, but vast in potential, these millimetre-sized bots could potentially be programmed to help in medical procedures, ocean cleanup and investigating dangerous compounds, among other things.

"They're neither a traditional robot nor a known species of animal, said researcher Joshua Bongard in a news release. It's a new class of artifact: a living, programmable organism."

In the introduction for the research published in Proceedings of the National Academy of Sciences (PNAS) on Monday, researchers point out that the traditional building blocks weve used for robots and tech -- steel, plastic, chemicals, etc. -- all degrade over time and can produce harmful ecological and health side-effects.

After realizing that the best self-renewing and biocompatible materials would be living systems themselves, researchers decided to create a method that designs completely biological machines from the ground up.

The bots are made out of stem cells taken from frog embryos -- specifically, an African clawed frog called xenopus laevis, which supplied the inspiration for the name xenobot. To design the xenobots, the possible configurations of different cells were first modeled on a supercomputer at the University of Vermont.

The designs then went to Tufts University, where the embryonic cells were collected and separated to develop into more specialized cells. Then, like sculptors (if sculptors used microsurgery forceps and electrodes), biologists manually shaped the cells into clumps that matched the computer designs.

Different structures were sketched out by the computer in accordance with the scientists goal for each xenobot.

For example, one xenobot was designed to be able to move purposely in a specific direction. To achieve this, researchers put cardiac cells on the bottom of the xenobot. These cells naturally contract and expand on their own, meaning that they could serve as the xenobots engine, or legs, and help move the rest of the organism, which was built out of more static skin cells.

In order to test if the living robots were truly moving the way they were designed to, and not just randomly, researchers performed a test that has stumped many a living creature.

They flipped the robot on its back. And just like a capsized turtle, it could no longer move.

When researchers created further designs for the bots, they found that they could design them to push microscopic objects, and even carry objects through a pouch.

"It's a step toward using computer-designed organisms for intelligent drug delivery," says Bongard.

The possible uses for these tiny robots are numerous, researchers say.

In biomedical settings, one could envision such biobots (made from the patients own cells) removing plaque from artery walls, identifying cancer, or settling down to differentiate or control events in locations of disease, the research paper suggests.

A robot made out of metal or steel generally has to be repaired by human hands if it sustains damage. One major benefit that researchers found of creating these robots out of living cells was how they reacted to physical damage.

A video taken by the researchers showed that when one of their organisms was cut almost in half by metal tweezers, the two sides of the wound simply stitched itself back together.

These living robots, researchers realized, could repair themselves automatically, something you cant do with typical machines, Bongard said.

Because they are living cells, they are also naturally biodegradable, Bongard pointed out. Once theyve fulfilled their purpose, theyre just dead skin cells, making them even more optimal for usage in medical or environmental research.

Although scientists have been increasingly manipulating genetics and biology, this is the first time that a programmable organism has been created from scratch, researchers say.

This new research takes scientists a step closer to answering just how different cells work together to execute all of the complex processes that occur every day in animals and humans.

"The big question in biology is to understand the algorithms that determine form and function," said co-leader Michael Levin in the press release. He directs the Center for Regenerative and Developmental Biology at Tufts.

"What actually determines the anatomy towards which cells co-operate? he asked. You look at the cells we've been building our xenobots with, and, genomically, they're frogs. It's 100 per cent frog DNA -- but these are not frogs. Then you ask, well, what else are these cells capable of building? As we've shown, these frog cells can be coaxed to make interesting living forms that are completely different from what their default anatomy would be.

Of course, a biological organism created and programmed by humans which is capable of healing itself might sound a little alarming. After all, one of the sponsors of the research is the Defense Advanced Research Projects Agency, which is affiliated with the U.S. military.

Researchers acknowledged in the press release that the implications around such technological and biological advancements can be worrying at times.

That fear is not unreasonable, Levin said. However, he believes that in order to move forward with science, we should not hold back from complex questions. This study is a direct contribution to getting a handle on what people are afraid of, which is unintended consequences.

"I think it's an absolute necessity for society going forward to get a better handle on systems where the outcome is very complex," Levin says. "A first step towards doing that is to explore: how do living systems decide what an overall behavior should be and how do we manipulate the pieces to get the behaviors we want?"

More on this story from CTVNews.ca

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The 'xenobot' is the worlds newest robot and it's made from living animal cells - The Loop

Cardiac Stem Cells Comments Off on The ‘xenobot’ is the worlds newest robot and it’s made from living animal cells – The Loop | January 17th, 2020

Plus, these new robots can heal themselves after being cut, giving them a longer life span. "They're neither a traditional robot nor a known species of animal. It's a new class of artifact: a living, programmable organism," notes Joshua Bongard, a computer scientist and robotics expert at the University of Vermont who co-led the new research.

The live robots were designed and developed on a supercomputer at UVM and then tested by biologists at Tufts University. The idea of manipulating living organisms and copying body forms for human benefit isn't something new. However, this is the first time scientists have developed biological machines from scratch.

The team led by lead author and doctoral student Sam Kriegman, used an evolutionary algorithm to develop thousands of candidate designs for the new life-forms on the Deep Green supercomputer and was published in PANS. The program was fed the basic rules about biophysics of what a single frog skin and cardiac cells were capable of.

Nearly a hundred independent algorithm runs were conducted to select the most promising designs. Next, the team at Tufts worked with microsurgeon to transfer the silicon designs into life. Stem cells from an African frog (Xenopus lavevis, giving the name Xenobots) were harvested in the embryos. Assembled into body forms, the cells began working together.

Many of our gadgets and other technologies are made of steel, plastic, silicon. While it makes it strong and flexible, it also creates an ecological imbalance and human health problems. Bongard notes that living tissues are weak and degrade quickly. "But organisms have 4.5 billion years of practice at regenerating themselves and going on for decades," he says.

Even when tissues die, they're harmless to the environment. What's more interesting is that the live robots were sliced into half and surprisingly, it stitched itself and kept going. "This is something you can't do with typical machines," Bongard says. This is organic computation, which the authors explain as the information is shared and cooperated between cells.

The reconfigured organisms were found moving coherently and could explore watery environments for days and weeks together. The immediate application the researchers are suggesting is healthcare, where the Xenobots can be sent to pick a payload like medicine and carry it to the specific place inside the patient.

What About Ill-Effects?

Of course, the concerns on rapid changes in technology and complex biological manipulations have been rising. "When we start to mess around with complex systems that we don't understand, we're going to get unintended consequences," the scientists agree. At the same time, researchers note that a better understanding of complex properties is essential for mankind to survive.

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Scientists Develop Live Robots With Frog Cells That Might Redefine Healthcare - Gizbot

Cardiac Stem Cells Comments Off on Scientists Develop Live Robots With Frog Cells That Might Redefine Healthcare – Gizbot | January 17th, 2020

Under normal circumstances the stem cells of frog embryos would skin and heart tissue of living beings, however, the progress of scientific knowledge has turned them into the first ever living robots.

Scientists from the University of Vermont with the help of special algorithms modified stem cells of a frog and created of them the first xenobot clumps of cells, capable of self-organization and even to transport tiny cargo. These colonies of 500-1000 cells do not resemble any living organism, or a naturally functioning body. At the same time they are different from the traditional robot is alive, but programmed organisms.

The opportunity to design a live guided machine, able to perform various tasks, from drug delivery to environmental cleanup, is truly revolutionary.

To create xenobot required a supercomputer and an algorithm that assemble in the desired configuration, hundreds of heart cells and skin tissue and simulates the result of such a living designer. The least successful configuration of the scientists involved in the experiment, culled, best preserved and improved using manipulations of the cells of the African frog Xenopus laevis microscopic tweezers and the electrode.

In one of the configurations, the scientists there is a hole in the center of the clot to reduce the resistance when driving. The experiment revealed that it can be used to attach to the get of goods for transportation.

After completing the Assembly of the fabric of biorobots began to operate at the programmed scenario: the skin cells began to group together, and provided the cardiac motor function. In an aqueous medium in the Petri dish these living machines can move up to a week without nutrient requirements energy supply inherent nature in the form of lipids and proteins.

Scientists say that this experiment gives an invaluable experience of knowing how cells communicate and exchange information:

From the point of view of the genome, its a frog. 100% DNA xenobot corresponds to the frog, but not frog. The question arises what else can be built from these cells? says biologist Michael Levin. This experiment shows us that frog cells can form life-forms that have nothing to do with the fact that they were anatomically.

However, living these robots can be called only conditionally they are not able to develop, you do not have the reproductive function and cant reproduce without the will of man, and, having exhausted all the resources of nutrients, they turn into lumps of dead cells (100% Biodegradability is a clear advantage of biological robots before the metal or plastic robots).

So far, the level of development xenobot seems completely harmless, but in the future they can enrich and nerve cells or even to turn into a new form of biological weapons.

Under normal circumstances the stem cells of frog embryos would skin and heart tissue of living beings, however, the progress of scientific knowledge has turned them into the first ever living robots.

Scientists from the University of Vermont with the help of special algorithms modified stem cells of a frog and created of them the first xenobot clumps of cells, capable of self-organization and even to transport tiny cargo. These colonies of 500-1000 cells do not resemble any living organism, or a naturally functioning body. At the same time they are different from the traditional robot is alive, but programmed organisms.

The opportunity to design a live guided machine, able to perform various tasks, from drug delivery to environmental cleanup, is truly revolutionary.

To create xenobot required a supercomputer and an algorithm that assemble in the desired configuration, hundreds of heart cells and skin tissue and simulates the result of such a living designer. The least successful configuration of the scientists involved in the experiment, culled, best preserved and improved using manipulations of the cells of the African frog Xenopus laevis microscopic tweezers and the electrode.

In one of the configurations, the scientists there is a hole in the center of the clot to reduce the resistance when driving. The experiment revealed that it can be used to attach to the get of goods for transportation.

After completing the Assembly of the fabric of biorobots began to operate at the programmed scenario: the skin cells began to group together, and provided the cardiac motor function. In an aqueous medium in the Petri dish these living machines can move up to a week without nutrient requirements energy supply inherent nature in the form of lipids and proteins.

Scientists say that this experiment gives an invaluable experience of knowing how cells communicate and exchange information:

From the point of view of the genome, its a frog. 100% DNA xenobot corresponds to the frog, but not frog. The question arises what else can be built from these cells? says biologist Michael Levin. This experiment shows us that frog cells can form life-forms that have nothing to do with the fact that they were anatomically.

However, living these robots can be called only conditionally they are not able to develop, you do not have the reproductive function and cant reproduce without the will of man, and, having exhausted all the resources of nutrients, they turn into lumps of dead cells (100% Biodegradability is a clear advantage of biological robots before the metal or plastic robots).

So far, the level of development xenobot seems completely harmless, but in the future they can enrich and nerve cells or even to turn into a new form of biological weapons.

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The first robots (xenobot) from living cells use cells of a frog - http://www.MICEtimes.asia

Cardiac Stem Cells Comments Off on The first robots (xenobot) from living cells use cells of a frog – www.MICEtimes.asia | January 17th, 2020

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Heart problems, graft-versus-host disease are concerns

A new study from Washington University School of Medicine in St. Louis suggests that bone marrow or blood stem cells from healthy donors can harbor extremely rare mutations that can cause health problems for the cancer patients who receive them. Such stem cell transplants are important for treating blood cancers, including acute myeloid leukemia. In the healthy bone marrow pictured, mature red blood cells are shown as small brownish-pink discs; red blood cells that are still developing are in deep blue; and developing white blood cells are in lighter blue.

A stem cell transplant also called a bone marrow transplant is a common treatment for blood cancers, such as acute myeloid leukemia (AML). Such treatment can cure blood cancers but also can lead to life-threatening complications, including heart problems and graft-versus-host disease, in which new immune cells from the donor attack a patients healthy tissues.

A new study from Washington University School of Medicine in St. Louis suggests that extremely rare, harmful genetic mutations present in healthy donors stem cells though not causing health problems in the donors may be passed on to cancer patients receiving stem cell transplants. The intense chemo- and radiation therapy prior to transplant and the immunosuppression given after allow cells with these rare mutations the opportunity to quickly replicate, potentially creating health problems for the patients who receive them, suggests the research, published Jan. 15 in the journal Science Translational Medicine.

Among the concerns are heart damage, graft-versus-host disease and possible new leukemias.

The study, involving samples from patients with AML and their stem cell donors, suggests such rare, harmful mutations are present in surprisingly young donors and can cause problems for recipients even if the mutations are so rare as to be undetectable in the donor by typical genome sequencing techniques. The research opens the door to a larger study that will investigate these rare mutations in many more healthy donors, potentially leading to ways to prevent or mitigate the health effects of such genetic errors in patients receiving stem cell transplants.

There have been suspicions that genetic errors in donor stem cells may be causing problems in cancer patients, but until now we didnt have a way to identify them because they are so rare, said senior author Todd E. Druley, MD, PhD, an associate professor of pediatrics. This study raises concerns that even young, healthy donors blood stem cells may have harmful mutations and provides strong evidence that we need to explore the potential effects of these mutations further.

Added co-author Sima T. Bhatt, MD, an assistant professor of pediatrics who treats pediatric patients with blood cancers at Siteman Kids at St. Louis Childrens Hospital and Washington University School of Medicine: Transplant physicians tend to seek younger donors because we assume this will lead to fewer complications. But we now see evidence that even young and healthy donors can have mutations that will have consequences for our patients. We need to understand what those consequences are if we are to find ways to modify them.

The study analyzed bone marrow from 25 adult patients with AML whose samples had been stored in a repository at Washington University. Samples from their healthy matched donors, who were unrelated to the patients, also were sequenced. The donors samples were provided by the Center for International Blood and Marrow Transplant Research in Milwaukee.

The 25 AML patients were chosen because they each had had samples banked at four separate times: before the transplant, at 30 days post-transplant, at 100 days post-transplant, and one year post-transplant.

Druley co-invented a technique called error-corrected sequencing, to identify extremely rare DNA mutations that would be missed by conventional genome sequencing. Typical next-generation sequencing techniques can correctly identify a mutation that is present in one in 100 cells. The new method, which can distinguish between true mutations and mistakes introduced by the sequencing machine, allows the researchers to find true mutations that are extremely rare those present in as few as one in 10,000 cells.

The healthy donors ranged in age from 20 to 58, with an average age of 26. The researchers sequenced 80 genes known to be associated with AML, and they identified at least one harmful genetic mutation in 11 of the 25 donors, or 44%. They further showed that 84% of all the various mutations identified in the donors samples were potentially harmful, and that 100% of the harmful mutations present in the donors later were found in the recipients. These harmful mutations also persisted over time, and many increased in frequency. Such data suggest the harmful mutations from the donor confer a survival advantage to the cells that harbor them.

We didnt expect this many young, healthy donors to have these types of mutations, Druley said. We also didnt expect 100% of the harmful mutations to be engrafted into the recipients. That was striking.

According to the researchers, the study raises questions about the origins of some of the well-known side effects of stem cell transplantation.

We see a trend between mutations from the donor that persist over time and the development of chronic graft-versus-host disease, said first author Wing Hing Wong, a doctoral student in Druleys lab. We plan to examine this more closely in a larger study.

Though the study was not large enough to establish a causal link, the researchers found that 75% of the patients who received at least one harmful mutation in the 80 genes that persisted over time developed chronic graft-versus-host disease. Among patients who did not receive mutations in the 80 genes, about 50% developed the condition. Because the study was small, this difference was not statistically significant, but it is evidence that the association should be studied more closely. In general, about half of all patients who receive a stem cell transplant go on to develop some form of graft-versus-host disease.

The most common mutation seen in the donors and the cancer patients studied is in a gene associated with heart disease. Healthy people with mutations in this gene are at higher risk of heart attack due to plaque buildup in the arteries.

We know that cardiac dysfunction is a major complication after a bone marrow transplant, but its always been attributed to toxicity from radiation or chemotherapy, Druley said. Its never been linked to mutations in the blood-forming cells. We cant make this claim definitively, but we have data to suggest we should study that in much more detail.

Added Bhatt: Now that weve also linked these mutations to graft-versus-host disease and cardiovascular problems, we have a larger study planned that we hope will answer some of the questions posed by this one.

This work was supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH), grant number R01CA211711; the Hyundai Quantum Award; the Leukemia and Lymphoma Society Scholar Award; the Eli Seth Matthews Leukemia Foundation; and the Kellsies Hope Foundation. The Center for International Blood and Marrow Transplant Research is supported by a Public Health Service Grant/Cooperative Agreement from the NCI, the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID), grant number 5U24CA076518; a Grant/Cooperative Agreement from NHLBI and NCI, grant number 1U24HL138660; a contract with Health Resources and Services Administration (HRSA/DHHS), number HHSH250201700006C; and the Office of Naval Research, grant numbers N00014-17-1-2388, N00014-17-1-2850 and N00014-18-1-2045. Support also was provided by a UKRI future leaders fellowship and by a CRUK Cambridge Centre Early Detection Programme group leader grant.

The Washington University Office of Technology Management has filed a patent application for Ultra-rare Variant Detection from Next-generation Sequencing, which has been licensed by Canopy Biosciences as RareSeq. Druley is a coinventor on this patent. Canopy Biosciences was not involved in the generation of the data presented.

Wong WH, Bhatt S, Trinkaus K, Pusic I, Elliott K, Mahajan N, Wan F, Switzer GE, Confer DL, DiPersio J, Pulsipher MA, Shah NN, Sees J, Bystry A, Blundell JR, Shaw BE, Druley TE. Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation. Science Translational Medicine. Jan. 15, 2020.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Mutations in donors' stem cells may cause problems for cancer patients - Washington University School of Medicine in St. Louis

Cardiac Stem Cells Comments Off on Mutations in donors’ stem cells may cause problems for cancer patients – Washington University School of Medicine in St. Louis | January 16th, 2020

CAMBRIDGE, Mass.--(BUSINESS WIRE)--bluebird bio, Inc. (Nasdaq: BLUE) announced the launch in Germany of ZYNTEGLO (autologous CD34+ cells encoding A-T87Q-globin gene), a one-time gene therapy for patients 12 years and older with transfusion-dependent -thalassemia (TDT) who do not have a 0/0 genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate but a human leukocyte antigen (HLA)-matched related HSC donor is not available. This is the first time ZYNTEGLO is commercially available.

TDT is a severe genetic disease caused by mutations in the -globin gene that result in significantly reduced or absent adult hemoglobin (HbA). In order to survive, people with TDT maintain hemoglobin (Hb) levels through lifelong chronic blood transfusions. These transfusions carry the risk of progressive multi-organ damage due to unavoidable iron overload. ZYNTEGLO is a one-time gene therapy that addresses the underlying genetic cause of TDT and offers patients the potential to become transfusion independent, which, once achieved, is expected to be lifelong.

Due to the highly technical and specialized nature of administering gene therapy in rare diseases, bluebird bio is working with institutions that have expertise in stem cell transplant as well as in treating patients with TDT to create qualified treatment centers that will administer ZYNTEGLO. bluebird bio has established a collaboration with University Hospital of Heidelberg as the first qualified treatment center in Germany.

In addition, bluebird has entered into value-based payment agreements with multiple statutory health insurances in Germany to help ensure patients and their healthcare providers have access to ZYNTEGLO and that payers only pay if the therapy delivers on its promise. bluebirds proposed innovative model is limited to five payments made in equal installments. An initial payment is made at the time of infusion. The four additional annual payments are only made if no transfusions for TDT are required for the patient.

For patients with TDT, lifelong chronic blood transfusions are required in order to survive. We are thrilled to announce that ZYNTEGLO will now be available for patients in the EU living with this severe disease, says Alison Finger, chief commercial officer, bluebird bio. In addition to confirming manufacturing readiness of our partner, apceth Biopharma GmbH, bluebird has also submitted a dossier to the Joint Federal Committee (G-BA) in Germany for drug benefit assessment. We would like to thank our collaborators for their commitment in helping us transform the healthcare system by accepting innovative payment models, and we look forward to treating our first commercial patient soon.

About LentiGlobin for -Thalassemia (autologous CD34+ cells encoding A-T87Q-globin gene)

The European Commission granted conditional marketing authorization for LentiGlobin for -thalassemia, to be marketed as ZYNTEGLO (autologous CD34+ cells encoding A-T87Q-globin gene) gene therapy, for patients 12 years and older with TDT who do not have a 0/0 genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate, but a human leukocyte antigen (HLA)-matched related HSC donor is not available.

TDT is a severe genetic disease caused by mutations in the -globin gene that result in reduced or significantly reduced hemoglobin (Hb). In order to survive, people with TDT maintain Hb levels through lifelong chronic blood transfusions. These transfusions carry the risk of progressive multi-organ damage due to unavoidable iron overload.

LentiGlobin for -thalassemia adds functional copies of a modified form of the -globin gene (A-T87Q-globin gene) into a patients own hematopoietic (blood) stem cells (HSCs). Once a patient has the A-T87Q-globin gene, they have the potential to produce HbAT87Q, which is gene therapy-derived hemoglobin, at levels that may eliminate or significantly reduce the need for transfusions.

Non-serious adverse events (AEs) observed during the HGB-204, HGB-207 and HGB-212 clinical studies that were attributed to LentiGlobin for -thalassemia were hot flush, dyspnoea, abdominal pain, pain in extremities, thrombocytopenia, leukopenia, neutropenia and non-cardiac chest pain. One serious adverse event (SAE) of thrombocytopenia was considered possibly related to LentiGlobin for -thalassemia for TDT.

Additional AEs observed in clinical studies were consistent with the known side effects of HSC collection and bone marrow ablation with busulfan, including SAEs of veno-occlusive disease.

The conditional marketing authorization for ZYNTEGLO is valid in the 28 member states of the EU as well as Iceland, Liechtenstein and Norway. For details, please see the Summary of Product Characteristics (SmPC).

The U.S. Food and Drug Administration (FDA) granted LentiGlobin for -thalassemia Orphan Drug status and Breakthrough Therapy designation for the treatment of TDT. LentiGlobin for -thalassemia is not approved in the United States.

bluebird bio has initiated the rolling BLA submission for approval in the U.S., and is engaged with the FDA in discussions regarding the requirements and timing of the various components of the rolling BLA submission. Subject to these ongoing discussions, the company is currently planning to complete the BLA submission in the first half of 2020.

LentiGlobin for -thalassemia continues to be evaluated in the ongoing Phase 3 Northstar-2 and Northstar-3 studies. For more information about the ongoing clinical studies, visit http://www.northstarclinicalstudies.com or clinicaltrials.gov and use identifier NCT02906202 for Northstar-2 (HGB-207) or NCT03207009 for Northstar-3 (HGB-212).

bluebird bio is conducting a long-term safety and efficacy follow-up study (LTF-303) for people who have participated in bluebird bio-sponsored clinical studies of LentiGlobin for -thalassemia. For more information visit: https://www.bluebirdbio.com/our-science/clinical-trials or clinicaltrials.gov and use identifier NCT02633943 for LTF-303.

About bluebird bio, Inc.

bluebird bio is pioneering gene therapy with purpose. From our Cambridge, Mass., headquarters, were developing gene therapies for severe genetic diseases and cancer, with the goal that people facing potentially fatal conditions with limited treatment options can live their lives fully. Beyond our labs, were working to positively disrupt the healthcare system to create access, transparency and education so that gene therapy can become available to all those who can benefit.

bluebird bio is a human company powered by human stories. Were putting our care and expertise to work across a spectrum of disorders including cerebral adrenoleukodystrophy, sickle cell disease, -thalassemia and multiple myeloma, using three gene therapy technologies: gene addition, cell therapy and (megaTAL-enabled) gene editing.

bluebird bio has additional nests in Seattle, Wash.; Durham, N.C.; and Zug, Switzerland. For more information, visit bluebirdbio.com.

Follow bluebird bio on social media: @bluebirdbio, LinkedIn, Instagram and YouTube.

ZYNTEGLO, LentiGlobin, and bluebird bio are trademarks of bluebird bio, Inc.

The full common name for ZYNTEGLO: A genetically modified autologous CD34+ cell enriched population that contains hematopoietic stem cells transduced with lentiviral vector encoding the A-T87Q-globin gene.

Forward-Looking Statements

This release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements regarding the Companys plans and expectations for the commercialization for ZYNTEGLO (autologous CD34+ cells encoding A-T87Q-globin gene, formerly LentiGlobin in TDT) to treat TDT, and the potential implications of clinical data for patients. Any forward-looking statements are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: the risk that the efficacy and safety results from our prior and ongoing clinical trials of ZYNTEGLO will not continue or be repeated in our ongoing or planned clinical trials of ZYNTEGLO; the risk that the current or planned clinical trials of ZYNTEGLO will be insufficient to support regulatory submissions or marketing approval in the US, or for additional patient populations in the EU; the risk that the production of HbAT87Q may not be sustained over extended periods of time; the risk that we may not secure adequate pricing or reimbursement to support continued development or commercialization of ZYNTEGLO; the risk that our collaborations with qualified treatment centers will not continue or be successful; and that the risk that commercial patients treated with ZYNTEGLO will not achieve or maintain transfusion independence. For a discussion of other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled Risk Factors in our most recent Form 10-Q, as well as discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and bluebird bio undertakes no duty to update this information unless required by law.

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bluebird bio Announces Launch in Germany of ZYNTEGLO (autologous CD34+ cells encoding A-T87Q-globin gene) Gene Therapy for Patients 12 Years and Older...

Cardiac Stem Cells Comments Off on bluebird bio Announces Launch in Germany of ZYNTEGLO (autologous CD34+ cells encoding A-T87Q-globin gene) Gene Therapy for Patients 12 Years and Older… | January 16th, 2020

The exosomes (or extracellular vesicles) released by stem cells may be the disruptive therapy for tackling age-related diseases doctors and patients have been waiting for. Despite over a decade and a half of hope and hype, stem cell therapy has failed to deliver on the promise.

Stem cell therapy once seemed beguilingly simple. As we age the number of stem cells in our bodies declines and degeneration increases.

The idea back in the early 2000s was that progenitor or adult stem cells (MSCs) could be given to patients as an unmatched (allogeneic) off-the-shelf drug and the administered cells would migrate to sites of damage or disease in the body.

Once there, it was thought, the cells would engraft and persist at these sites of injury and directly replace the patients own damaged cells. The administered cells treating cardiac disease would become a part of the patients heart tissue, for example.

It was thought that by injecting additional stem cells into the body, the new cells would transform the way that we treat certain conditions such as joint pain, stroke and cardiac degeneration. Animal studies and early human trials appeared to bear the idea out.

But nearly 20 years on, the general safety and efficacy of stem cell therapy has still not been proven, experts from the US Food and Drug Administration (FDA) recently concluded in the New England Journal of Medicine.1

Despite the earlier promise, cellular therapy for regenerative medicine is struggling to get approvals and to generate sales. Only a few allogeneic off-the-shelf cellular therapies have been approved for sale worldwide for regenerative medicine, despite huge investments2.

It turned out that a therapy based on transplanting living cells from donors into the patients body was anything but simple.

The first key issue with stem cell therapy is the question mark over safety. Introducing foreign living cells into a system as complex as the human body is challenging.

Predicting the cells behaviour once injected is a problem, FDA experts say.

A growing list of cautionary examples catalogue how things can go wrong when unproven stem cell therapies are used in the clinic; from a kidney failure patient who developed tumours following stem cell therapy, to patients with an age-related eye condition called macular degeneration, who were left blinded by their therapy given at a US clinic3.

In late 2018 and after infections linked to unapproved stem cell treatments sent 12 people to hospital, the FDA issued a stern warning about the cell products4.

Some autologous therapies using the patients own cells have also become notorious in certain countries and the subject of doubtful or dangerous medical tourism.

Today, the only stem cell therapy that has received FDA approval in the regenerative medicine field is the use of blood-forming stem cells for patients with specific blood production disorders.

Stem cells appear to be making little progress toward FDA-approved clinical use. Little wonder, then, that regenerative medicine researchers are increasingly turning to exosomes: packets of beneficial biomolecules released by stem cells.

We now know that the old working hypothesis for how stem cells exert their regenerative effects was wrong. The transplanted stem cells dont stick around long in the recipients body to replace damaged cells; most are cleared within a week.

As researchers from Oxford5 to Scripps6 have now concluded, its the exosomes stem cells release, rather than the cells themselves, that impart the regenerative benefit.

Exosomes are being described as the secret sauce of stem cells. Exosome therapy would avoid all the problems of a therapy based on live stem cells and yet harness a natural regenerative capability from stem cells.

Tellingly, some biotech stocks established back in the early 2000s as stem cell companies have shifted their focus to exosome research.

Exosome drugs could be harvested from stem cells housed in a bioreactor and then purified as a proper drug product to be administered by injection or infusion.

Exosomes should be a simpler, safer, lower cost, more easily stored and transported, alternative to stem cells.

Critically, exosomes are inherently less risky that live stem cell transplants. Exosomes cannot replicate; they cannot transform into malignant cells or other harmful cell types; they are less likely to trigger an immunogenic response; they cannot be infected with virus.

As a further demonstration of their safety, blood plasma contains high concentrations of unmatched exosomes, and blood transfusions have been carried out in hospitals for decades.

And exosomes should have an efficacy advantage, too. Being much smaller than whole cells, exosomes can circulate much more easily through the body to reach sites of injury or disease and trigger healing.

Early academic clinical studies are starting to prove exosomes potential. A recent placebo-controlled trial on 40 patients with advanced chronic kidney disease showed that the patients receiving exosomes saw enhanced kidney function at 12 months after treatment and no adverse events in the treatment group7.

Exosomes administered to patients could exert their regenerative effects in a number of ways giving treatment by exosomes multiple shots at goal.

Some degeneration, such as Parkinsons Disease, is due to a loss of specialised cells over time. Struggling cells that take up exosomes can be rescued from programmed cell death (apoptosis), and restored to health, thanks to the regenerative genetic material and the protein and lipid cellular building blocks that the exosome delivers.

Degeneration with age has also been associated with an increase in senescence cells. Senescent cells are like zombie cells that dont undergo normal clearance, yet cannot divide and proliferate to generate new tissue.

Recent research points to a benefit in animal models of human disease when the number of senescent cells is reduced. In 2019 researchers published that exosomes and vesicles from stem cells can alleviate cellular aging (senescence) in cells exposed to the exosomes/vesicles8.

Exosomes can also play a role in a recently discovered, previously unsuspected regenerative process in our bodies. Exosomes can trigger fully differentiated, specialised cells such as liver cells (hepatocytes) to a de-differentiate into a more stem cell-like state cell type9 and then maintain a pool of progenitor cells that can replenish the damaged liver with new cells10.

This same mechanism could be used to treat cardiac disease (e.g. cardiac ischemia where a lack of blood flow leads to cardiac muscle cell death). Normally a damaged heart fails to regenerate and becomes fibrotic with scar tissue.

Unfortunately, the scar tissue doesnt have the capacity to beat like cardiomyocytes, so increased fibrosis leads to progressive loss of heart pumping ejected volume and impairment or death. But using exosomes to reprogram the patients own heart muscle cells into cardiac progenitor stem cells offers a new way to treat cardiac damage and drive regeneration.

Exosomes from stem cells could be a better medicine than live stem cells a way to harness stem cells regenerative power without all the problems and disappointment.

But while stem cells secrete trillions of exosomes naturally, efficient separation and purification of exosomes has proven to be very difficult indeed11. Until now.

Exopharms proprietary LEAP technology is a robust and reliable method for producing a well-defined set of proprietary pharmaceutical-grade exosome product as a next-generation cell-free regenerative medicine.

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The Next Big Thing: Exosomes versus Stem Cells

Cardiac Stem Cells Comments Off on The Next Big Thing: Exosomes versus Stem Cells | January 14th, 2020

For many years, researchers have been seeking to understand the body's ability to repair and replace the cells and tissues of some organs, but not others. After years of work pursuing the how and why of seemingly indiscriminant cell repair mechanisms, scientists have now focused their attention on adult stem cells. It has long been known that stem cells are capable of renewing themselves and that they can generate multiple cell types. Today, there is new evidence that stem cells are present in far more tissues and organs than once thought and that these cells are capable of developing into more kinds of cells than previously imagined. Efforts are now underway to harness stem cells and to take advantage of this new found capability, with the goal of devising new and more effective treatments for a host of diseases and disabilities. What lies ahead for the use of adult stem cells is unknown, but it is certain that there are many research questions to be answered and that these answers hold great promise for the future.

Adult stem cells, like all stem cells, share at least two characteristics. First, they can make identical copies of themselves for long periods of time; this ability to proliferate is referred to as long-term self-renewal. Second, they can give rise to mature cell types that have characteristic morphologies (shapes) and specialized functions. Typically, stem cells generate an intermediate cell type or types before they achieve their fully differentiated state. The intermediate cell is called a precursor or progenitor cell. Progenitor or precursor cells in fetal or adult tissues are partly differentiated cells that divide and give rise to differentiated cells. Such cells are usually regarded as "committed" to differentiating along a particular cellular development pathway, although this characteristic may not be as definitive as once thought [82] (see Figure 4.1. Distinguishing Features of Progenitor/Precursor Cells and Stem Cells).

Figure 4.1. Distinguishing Features of Progenitor/Precursor Cells and Stem Cells. A stem cell is an unspecialized cell that is capable of replicating or self renewing itself and developing into specialized cells of a variety of cell types. The product of a stem cell undergoing division is at least one additional stem cell that has the same capabilities of the originating cell. Shown here is an example of a hematopoietic stem cell producing a second generation stem cell and a neuron. A progenitor cell (also known as a precursor cell) is unspecialized or has partial characteristics of a specialized cell that is capable of undergoing cell division and yielding two specialized cells. Shown here is an example of a myeloid progenitor/precursor undergoing cell division to yield two specialized cells (a neutrophil and a red blood cell).

( 2001 Terese Winslow, Lydia Kibiuk)

Adult stem cells are rare. Their primary functions are to maintain the steady state functioning of a cellcalled homeostasisand, with limitations, to replace cells that die because of injury or disease [44, 58]. For example, only an estimated 1 in 10,000 to 15,000 cells in the bone marrow is a hematopoietic (bloodforming) stem cell (HSC) [105]. Furthermore, adult stem cells are dispersed in tissues throughout the mature animal and behave very differently, depending on their local environment. For example, HSCs are constantly being generated in the bone marrow where they differentiate into mature types of blood cells. Indeed, the primary role of HSCs is to replace blood cells [26] (see Chapter 5. Hematopoietic Stem Cells). In contrast, stem cells in the small intestine are stationary, and are physically separated from the mature cell types they generate. Gut epithelial stem cells (or precursors) occur at the bases of cryptsdeep invaginations between the mature, differentiated epithelial cells that line the lumen of the intestine. These epithelial crypt cells divide fairly often, but remain part of the stationary group of cells they generate [93].

Unlike embryonic stem cells, which are defined by their origin (the inner cell mass of the blastocyst), adult stem cells share no such definitive means of characterization. In fact, no one knows the origin of adult stem cells in any mature tissue. Some have proposed that stem cells are somehow set aside during fetal development and restrained from differentiating. Definitions of adult stem cells vary in the scientific literature range from a simple description of the cells to a rigorous set of experimental criteria that must be met before characterizing a particular cell as an adult stem cell. Most of the information about adult stem cells comes from studies of mice. The list of adult tissues reported to contain stem cells is growing and includes bone marrow, peripheral blood, brain, spinal cord, dental pulp, blood vessels, skeletal muscle, epithelia of the skin and digestive system, cornea, retina, liver, and pancreas.

In order to be classified as an adult stem cell, the cell should be capable of self-renewal for the lifetime of the organism. This criterion, although fundamental to the nature of a stem cell, is difficult to prove in vivo. It is nearly impossible, in an organism as complex as a human, to design an experiment that will allow the fate of candidate adult stem cells to be identified in vivo and tracked over an individual's entire lifetime.

Ideally, adult stem cells should also be clonogenic. In other words, a single adult stem cell should be able to generate a line of genetically identical cells, which then gives rise to all the appropriate, differentiated cell types of the tissue in which it resides. Again, this property is difficult to demonstrate in vivo; in practice, scientists show either that a stem cell is clonogenic in vitro, or that a purified population of candidate stem cells can repopulate the tissue.

An adult stem cell should also be able to give rise to fully differentiated cells that have mature phenotypes, are fully integrated into the tissue, and are capable of specialized functions that are appropriate for the tissue. The term phenotype refers to all the observable characteristics of a cell (or organism); its shape (morphology); interactions with other cells and the non-cellular environment (also called the extracellular matrix); proteins that appear on the cell surface (surface markers); and the cell's behavior (e.g., secretion, contraction, synaptic transmission).

The majority of researchers who lay claim to having identified adult stem cells rely on two of these characteristicsappropriate cell morphology, and the demonstration that the resulting, differentiated cell types display surface markers that identify them as belonging to the tissue. Some studies demonstrate that the differentiated cells that are derived from adult stem cells are truly functional, and a few studies show that cells are integrated into the differentiated tissue in vivo and that they interact appropriately with neighboring cells. At present, there is, however, a paucity of research, with a few notable exceptions, in which researchers were able to conduct studies of genetically identical (clonal) stem cells. In order to fully characterize the regenerating and self-renewal capabilities of the adult stem cell, and therefore to truly harness its potential, it will be important to demonstrate that a single adult stem cell can, indeed, generate a line of genetically identical cells, which then gives rise to all the appropriate, differentiated cell types of the tissue in which it resides.

Adult stem cells have been identified in many animal and human tissues. In general, three methods are used to determine whether candidate adult stem cells give rise to specialized cells. Adult stem cells can be labeled in vivo and then they can be tracked. Candidate adult stem cells can also be isolated and labeled and then transplanted back into the organism to determine what becomes of them. Finally, candidate adult stem cells can be isolated, grown in vitro and manipulated, by adding growth factors or introducing genes that help determine what differentiated cells types they will yield. For example, currently, scientists believe that stem cells in the fetal and adult brain divide and give rise to more stem cells or to several types of precursor cells, which give rise to nerve cells (neurons), of which there are many types.

It is often difficultif not impossibleto distinguish adult, tissue-specific stem cells from progenitor cells, which are found in fetal or adult tissues and are partly differentiated cells that divide and give rise to differentiated cells. These are cells found in many organs that are generally thought to be present to replace cells and maintain the integrity of the tissue. Progenitor cells give rise to certain types of cellssuch as the blood cells known as T lymphocytes, B lymphocytes, and natural killer cellsbut are not thought to be capable of developing into all the cell types of a tissue and as such are not truly stem cells. The current wave of excitement over the existence of stem cells in many adult tissues is perhaps fueling claims that progenitor or precursor cells in those tissues are instead stem cells. Thus, there are reports of endothelial progenitor cells, skeletal muscle stem cells, epithelial precursors in the skin and digestive system, as well as some reports of progenitors or stem cells in the pancreas and liver. A detailed summary of some of the evidence for the existence of stem cells in various tissues and organs is presented later in the chapter.

It was not until recently that anyone seriously considered the possibility that stem cells in adult tissues could generate the specialized cell types of another type of tissue from which they normally resideeither a tissue derived from the same embryonic germ layer or from a different germ layer (see Table 1.1. Embryonic Germ Layers From Which Differentiated Tissues Develop). For example, studies have shown that blood stem cells (derived from mesoderm) may be able to generate both skeletal muscle (also derived from mesoderm) and neurons (derived from ectoderm). That realization has been triggered by a flurry of papers reporting that stem cells derived from one adult tissue can change their appearance and assume characteristics that resemble those of differentiated cells from other tissues.

The term plasticity, as used in this report, means that a stem cell from one adult tissue can generate the differentiated cell types of another tissue. At this time, there is no formally accepted name for this phenomenon in the scientific literature. It is variously referred to as "plasticity" [15, 52], "unorthodox differentiation" [10] or "transdifferentiation" [7, 54].

To be able to claim that adult stem cells demonstrate plasticity, it is first important to show that a cell population exists in the starting tissue that has the identifying features of stem cells. Then, it is necessary to show that the adult stem cells give rise to cell types that normally occur in a different tissue. Neither of these criteria is easily met. Simply proving the existence of an adult stem cell population in a differentiated tissue is a laborious process. It requires that the candidate stem cells are shown to be self-renewing, and that they can give rise to the differentiated cell types that are characteristic of that tissue.

To show that the adult stem cells can generate other cell types requires them to be tracked in their new environment, whether it is in vitro or in vivo. In general, this has been accomplished by obtaining the stem cells from a mouse that has been genetically engineered to express a molecular tag in all its cells. It is then necessary to show that the labeled adult stem cells have adopted key structural and biochemical characteristics of the new tissue they are claimed to have generated. Ultimatelyand most importantlyit is necessary to demonstrate that the cells can integrate into their new tissue environment, survive in the tissue, and function like the mature cells of the tissue.

In the experiments reported to date, adult stem cells may assume the characteristics of cells that have developed from the same primary germ layer or a different germ layer (see Figure 4.2. Preliminary Evidence of Plasticity Among Nonhuman Adult Stem Cells). For example, many plasticity experiments involve stem cells derived from bone marrow, which is a mesodermal derivative. The bone marrow stem cells may then differentiate into another mesodermally derived tissue such as skeletal muscle [28, 43], cardiac muscle [51, 71] or liver [4, 54, 97].

Figure 4.2. Preliminary Evidence of Plasticity Among Nonhuman Adult Stem Cells.

( 2001 Terese Winslow, Lydia Kibiuk, Caitlin Duckwall)

Alternatively, adult stem cells may differentiate into a tissue thatduring normal embryonic developmentwould arise from a different germ layer. For example, bone marrow-derived cells may differentiate into neural tissue, which is derived from embryonic ectoderm [15, 65]. Andreciprocallyneural stem cell lines cultured from adult brain tissue may differentiate to form hematopoietic cells [13], or even give rise to many different cell types in a chimeric embryo [17]. In both cases cited above, the cells would be deemed to show plasticity, but in the case of bone marrow stem cells generating brain cells, the finding is less predictable.

In order to study plasticity within and across germ layer lines, the researcher must be sure that he/she is using only one kind of adult stem cell. The vast majority of experiments on plasticity have been conducted with adult stem cells derived either from the bone marrow or the brain. The bone marrow-derived cells are sometimes sortedusing a panel of surface markersinto populations of hematopoietic stem cells or bone marrow stromal cells [46, 54, 71]. The HSCs may be highly purified or partially purified, depending on the conditions used. Another way to separate population of bone marrow cells is by fractionation to yield cells that adhere to a growth substrate (stromal cells) or do not adhere (hematopoietic cells) [28].

To study plasticity of stem cells derived from the brain, the researcher must overcome several problems. Stem cells from the central nervous system (CNS), unlike bone marrow cells, do not occur in a single, accessible location. Instead, they are scattered in three places, at least in rodent brainthe tissue around the lateral ventricles in the forebrain, a migratory pathway for the cells that leads from the ventricles to the olfactory bulbs, and the hippocampus. Many of the experiments with CNS stem cells involve the formation of neurospheres, round aggregates of cells that are sometimes clonally derived. But it is not possible to observe cells in the center of a neurosphere, so to study plasticity in vitro, the cells are usually dissociated and plated in monolayers. To study plasticity in vivo, the cells may be dissociated before injection into the circulatory system of the recipient animal [13], or injected as neurospheres [17].

The differentiated cell types that result from plasticity are usually reported to have the morphological characteristics of the differentiated cells and to display their characteristic surface markers. In reports that transplanted adult stem cells show plasticity in vivo, the stem cells typically are shown to have integrated into a mature host tissue and assumed at least some of its characteristics [15, 28, 51, 65, 71]. Many plasticity experiments involve injury to a particular tissue, which is intended to model a particular human disease or injury [13, 54, 71]. However, there is limited evidence to date that such adult stem cells can generate mature, fully functional cells or that the cells have restored lost function in vivo [54]. Most of the studies that show the plasticity of adult stem cells involve cells that are derived from the bone marrow [15, 28, 54, 65, 77] or brain [13, 17]. To date, adult stem cells are best characterized in these two tissues, which may account for the greater number of plasticity studies based on bone marrow and brain. Collectively, studies on plasticity suggest that stem cell populations in adult mammals are not fixed entities, and that after exposure to a new environment, they may be able to populate other tissues and possibly differentiate into other cell types.

It is not yet possible to say whether plasticity occurs normally in vivo. Some scientists think it may [14, 64], but as yet there is no evidence to prove it. Also, it is not yet clear to what extent plasticity can occur in experimental settings, and howor whetherthe phenomenon can be harnessed to generate tissues that may be useful for therapeutic transplantation. If the phenomenon of plasticity is to be used as a basis for generating tissue for transplantation, the techniques for doing it will need to be reproducible and reliable (see Chapter 10. Assessing Human Stem Cell Safety). In some cases, debate continues about observations that adult stem cells yield cells of tissue types different than those from which they were obtained [7, 68].

More than 30 years ago, Altman and Das showed that two regions of the postnatal rat brain, the hippocampus and the olfactory bulb, contain dividing cells that become neurons [5, 6]. Despite these reports, the prevailing view at the time was that nerve cells in the adult brain do not divide. In fact, the notion that stem cells in the adult brain can generate its three major cell typesastrocytes and oligodendrocytes, as well as neuronswas not accepted until far more recently. Within the past five years, a series of studies has shown that stem cells occur in the adult mammalian brain and that these cells can generate its three major cell lineages [35, 48, 63, 66, 90, 96, 104] (see Chapter 8. Rebuilding the Nervous System with Stem Cells).

Today, scientists believe that stem cells in the fetal and adult brain divide and give rise to more stem cells or to several types of precursor cells. Neuronal precursors (also called neuroblasts) divide and give rise to nerve cells (neurons), of which there are many types. Glial precursors give rise to astrocytes or oligodendrocytes. Astrocytes are a kind of glial cell, which lend both mechanical and metabolic support for neurons; they make up 70 to 80 percent of the cells of the adult brain. Oligodendrocytes make myelin, the fatty material that ensheathes nerve cell axons and speeds nerve transmission. Under normal, in vivo conditions, neuronal precursors do not give rise to glial cells, and glial precursors do not give rise to neurons. In contrast, a fetal or adult CNS (central nervous systemthe brain and spinal cord) stem cell may give rise to neurons, astrocytes, or oligodendrocytes, depending on the signals it receives and its three-dimensional environment within the brain tissue. There is now widespread consensus that the adult mammalian brain does contain stem cells. However, there is no consensus about how many populations of CNS stem cells exist, how they may be related, and how they function in vivo. Because there are no markers currently available to identify the cells in vivo, the only method for testing whether a given population of CNS cells contains stem cells is to isolate the cells and manipulate them in vitro, a process that may change their intrinsic properties [67].

Despite these barriers, three groups of CNS stem cells have been reported to date. All occur in the adult rodent brain and preliminary evidence indicates they also occur in the adult human brain. One group occupies the brain tissue next to the ventricles, regions known as the ventricular zone and the sub-ventricular zone (see discussion below). The ventricles are spaces in the brain filled with cerebrospinal fluid. During fetal development, the tissue adjacent to the ventricles is a prominent region of actively dividing cells. By adulthood, however, this tissue is much smaller, although it still appears to contain stem cells [70].

A second group of adult CNS stem cells, described in mice but not in humans, occurs in a streak of tissue that connects the lateral ventricle and the olfactory bulb, which receives odor signals from the nose. In rodents, olfactory bulb neurons are constantly being replenished via this pathway [59, 61]. A third possible location for stem cells in adult mouse and human brain occurs in the hippocampus, a part of the brain thought to play a role in the formation of certain kinds of memory [27, 34].

Central Nervous System Stem Cells in the Subventricular Zone. CNS stem cells found in the forebrain that surrounds the lateral ventricles are heterogeneous and can be distinguished morphologically. Ependymal cells, which are ciliated, line the ventricles. Adjacent to the ependymal cell layer, in a region sometimes designated as the subependymal or subventricular zone, is a mixed cell population that consists of neuroblasts (immature neurons) that migrate to the olfactory bulb, precursor cells, and astrocytes. Some of the cells divide rapidly, while others divide slowly. The astrocyte-like cells can be identified because they contain glial fibrillary acidic protein (GFAP), whereas the ependymal cells stain positive for nestin, which is regarded as a marker of neural stem cells. Which of these cells best qualifies as a CNS stem cell is a matter of debate [76].

A recent report indicates that the astrocytes that occur in the subventricular zone of the rodent brain act as neural stem cells. The cells with astrocyte markers appear to generate neurons in vivo, as identified by their expression of specific neuronal markers. The in vitro assay to demonstrate that these astrocytes are, in fact, stem cells involves their ability to form neurospheresgroupings of undifferentiated cells that can be dissociated and coaxed to differentiate into neurons or glial cells [25]. Traditionally, these astrocytes have been regarded as differentiated cells, not as stem cells and so their designation as stem cells is not universally accepted.

A series of similar in vitro studies based on the formation of neurospheres was used to identify the subependymal zone as a source of adult rodent CNS stem cells. In these experiments, single, candidate stem cells derived from the subependymal zone are induced to give rise to neurospheres in the presence of mitogenseither epidermal growth factor (EGF) or fibroblast growth factor-2 (FGF-2). The neurospheres are dissociated and passaged. As long as a mitogen is present in the culture medium, the cells continue forming neurospheres without differentiating. Some populations of CNS cells are more responsive to EGF, others to FGF [100]. To induce differentiation into neurons or glia, cells are dissociated from the neurospheres and grown on an adherent surface in serum-free medium that contains specific growth factors. Collectively, the studies demonstrate that a population of cells derived from the adult rodent brain can self-renew and differentiate to yield the three major cell types of the CNS cells [41, 69, 74, 102].

Central Nervous System Stem Cells in the Ventricular Zone. Another group of potential CNS stem cells in the adult rodent brain may consist of the ependymal cells themselves [47]. Ependymal cells, which are ciliated, line the lateral ventricles. They have been described as non-dividing cells [24] that function as part of the blood-brain barrier [22]. The suggestion that ependymal cells from the ventricular zone of the adult rodent CNS may be stem cells is therefore unexpected. However, in a recent study, in which two molecular tagsthe fluorescent marker Dil, and an adenovirus vector carrying lacZ tagswere used to label the ependymal cells that line the entire CNS ventricular system of adult rats, it was shown that these cells could, indeed, act as stem cells. A few days after labeling, fluorescent or lacZ+ cells were observed in the rostral migratory stream (which leads from the lateral ventricle to the olfactory bulb), and then in the olfactory bulb itself. The labeled cells in the olfactory bulb also stained for the neuronal markers III tubulin and Map2, which indicated that ependymal cells from the ventricular zone of the adult rat brain had migrated along the rostral migratory stream to generate olfactory bulb neurons in vivo [47].

To show that Dil+ cells were neural stem cells and could generate astrocytes and oligodendrocytes as well as neurons, a neurosphere assay was performed in vitro. Dil-labeled cells were dissociated from the ventricular system and cultured in the presence of mitogen to generate neurospheres. Most of the neurospheres were Dil+; they could self-renew and generate neurons, astrocytes, and oligodendrocytes when induced to differentiate. Single, Dil+ ependymal cells isolated from the ventricular zone could also generate self-renewing neurospheres and differentiate into neurons and glia.

To show that ependymal cells can also divide in vivo, bromodeoxyuridine (BrdU) was administered in the drinking water to rats for a 2- to 6-week period. Bromodeoxyuridine (BrdU) is a DNA precursor that is only incorporated into dividing cells. Through a series of experiments, it was shown that ependymal cells divide slowly in vivo and give rise to a population of progenitor cells in the subventricular zone [47]. A different pattern of scattered BrdU-labeled cells was observed in the spinal cord, which suggested that ependymal cells along the central canal of the cord occasionally divide and give rise to nearby ependymal cells, but do not migrate away from the canal.

Collectively, the data suggest that CNS ependymal cells in adult rodents can function as stem cells. The cells can self-renew, and most proliferate via asymmetrical division. Many of the CNS ependymal cells are not actively dividing (quiescent), but they can be stimulated to do so in vitro (with mitogens) or in vivo (in response to injury). After injury, the ependymal cells in the spinal cord only give rise to astrocytes, not to neurons. How and whether ependymal cells from the ventricular zone are related to other candidate populations of CNS stem cells, such as those identified in the hippocampus [34], is not known.

Are ventricular and subventricular zone CNS stem cells the same population? These studies and other leave open the question of whether cells that directly line the ventriclesthose in the ventricular zoneor cells that are at least a layer removed from this zonein the subventricular zone are the same population of CNS stem cells. A new study, based on the finding that they express different genes, confirms earlier reports that the ventricular and subventricular zone cell populations are distinct. The new research utilizes a technique called representational difference analysis, together with cDNA microarray analysis, to monitor the patterns of gene expression in the complex tissue of the developing and postnatal mouse brain. The study revealed the expression of a panel of genes known to be important in CNS development, such as L3-PSP (which encodes a phosphoserine phosphatase important in cell signaling), cyclin D2 (a cell cycle gene), and ERCC-1 (which is important in DNA excision repair). All of these genes in the recent study were expressed in cultured neurospheres, as well as the ventricular zone, the subventricular zone, and a brain area outside those germinal zones. This analysis also revealed the expression of novel genes such as A16F10, which is similar to a gene in an embryonic cancer cell line. A16F10 was expressed in neurospheres and at high levels in the subventricular zone, but not significantly in the ventricular zone. Interestingly, several of the genes identified in cultured neurospheres were also expressed in hematopoietic cells, suggesting that neural stem cells and blood-forming cells may share aspects of their genetic programs or signaling systems [38]. This finding may help explain recent reports that CNS stem cells derived from mouse brain can give rise to hematopoietic cells after injection into irradiated mice [13].

Central Nervous System Stem Cells in the Hippocampus. The hippocampus is one of the oldest parts of the cerebral cortex, in evolutionary terms, and is thought to play an important role in certain forms of memory. The region of the hippocampus in which stem cells apparently exist in mouse and human brains is the subgranular zone of the dentate gyrus. In mice, when BrdU is used to label dividing cells in this region, about 50% of the labeled cells differentiate into cells that appear to be dentate gyrus granule neurons, and 15% become glial cells. The rest of the BrdU-labeled cells do not have a recognizable phenotype [90]. Interestingly, many, if not all the BrdU-labeled cells in the adult rodent hippocampus occur next to blood vessels [33].

In the human dentate gyrus, some BrdU-labeled cells express NeuN, neuron-specific enolase, or calbindin, all of which are neuronal markers. The labeled neuron-like cells resemble dentate gyrus granule cells, in terms of their morphology (as they did in mice). Other BrdU-labeled cells express glial fibrillary acidic protein (GFAP) an astrocyte marker. The study involved autopsy material, obtained with family consent, from five cancer patients who had been injected with BrdU dissolved in saline prior to their death for diagnostic purposes. The patients ranged in age from 57 to 72 years. The greatest number of BrdU-labeled cells were identified in the oldest patient, suggesting that new neuron formation in the hippocampus can continue late in life [27].

Fetal Central Nervous System Stem Cells. Not surprisingly, fetal stem cells are numerous in fetal tissues, where they are assumed to play an important role in the expansion and differentiation of all tissues of the developing organism. Depending on the developmental stage of an animal, fetal stem cells and precursor cellswhich arise from stem cellsmay make up the bulk of a tissue. This is certainly true in the brain [48], although it has not been demonstrated experimentally in many tissues.

It may seem obvious that the fetal brain contains stem cells that can generate all the types of neurons in the brain as well as astrocytes and oligodendrocytes, but it was not until fairly recently that the concept was proven experimentally. There has been a long-standing question as to whether or not the same cell type gives rise to both neurons and glia. In studies of the developing rodent brain, it has now been shown that all the major cell types in the fetal brain arise from a common population of progenitor cells [20, 34, 48, 80, 108].

Neural stem cells in the mammalian fetal brain are concentrated in seven major areas: olfactory bulb, ependymal (ventricular) zone of the lateral ventricles (which lie in the forebrain), subventricular zone (next to the ependymal zone), hippocampus, spinal cord, cerebellum (part of the hindbrain), and the cerebral cortex. Their number and pattern of development vary in different species. These cells appear to represent different stem cell populations, rather than a single population of stem cells that is dispersed in multiple sites. The normal development of the brain depends not only on the proliferation and differentiation of these fetal stem cells, but also on a genetically programmed process of selective cell death called apoptosis [76].

Little is known about stem cells in the human fetal brain. In one study, however, investigators derived clonal cell lines from CNS stem cells isolated from the diencephalon and cortex of human fetuses, 10.5 weeks post-conception [103]. The study is unusual, not only because it involves human CNS stem cells obtained from fetal tissue, but also because the cells were used to generate clonal cell lines of CNS stem cells that generated neurons, astrocytes, and oligodendrocytes, as determined on the basis of expressed markers. In a few experiments described as "preliminary," the human CNS stem cells were injected into the brains of immunosuppressed rats where they apparently differentiated into neuron-like cells or glial cells.

In a 1999 study, a serum-free growth medium that included EGF and FGF2 was devised to grow the human fetal CNS stem cells. Although most of the cells died, occasionally, single CNS stem cells survived, divided, and ultimately formed neurospheres after one to two weeks in culture. The neurospheres could be dissociated and individual cells replated. The cells resumed proliferation and formed new neurospheres, thus establishing an in vitro system that (like the system established for mouse CNS neurospheres) could be maintained up to 2 years. Depending on the culture conditions, the cells in the neurospheres could be maintained in an undifferentiated dividing state (in the presence of mitogen), or dissociated and induced to differentiate (after the removal of mitogen and the addition of specific growth factors to the culture medium). The differentiated cells consisted mostly of astrocytes (75%), some neurons (13%) and rare oligodendrocytes (1.2%). The neurons generated under these conditions expressed markers indicating they were GABAergic, [the major type of inhibitory neuron in the mammalian CNS responsive to the amino acid neurotransmitter, gammaaminobutyric acid (GABA)]. However, catecholamine-like cells that express tyrosine hydroxylase (TH, a critical enzyme in the dopamine-synthesis pathway) could be generated, if the culture conditions were altered to include different medium conditioned by a rat glioma line (BB49). Thus, the report indicates that human CNS stem cells obtained from early fetuses can be maintained in vitro for a long time without differentiating, induced to differentiate into the three major lineages of the CNS (and possibly two kinds of neurons, GABAergic and TH-positive), and engraft (in rats) in vivo [103].

Central Nervous System Neural Crest Stem Cells. Neural crest cells differ markedly from fetal or adult neural stem cells. During fetal development, neural crest cells migrate from the sides of the neural tube as it closes. The cells differentiate into a range of tissues, not all of which are part of the nervous system [56, 57, 91]. Neural crest cells form the sympathetic and parasympathetic components of the peripheral nervous system (PNS), including the network of nerves that innervate the heart and the gut, all the sensory ganglia (groups of neurons that occur in pairs along the dorsal surface of the spinal cord), and Schwann cells, which (like oligodendrocytes in the CNS) make myelin in the PNS. The non-neural tissues that arise from the neural crest are diverse. They populate certain hormone-secreting glandsincluding the adrenal medulla and Type I cells in the carotid bodypigment cells of the skin (melanocytes), cartilage and bone in the face and skull, and connective tissue in many parts of the body [76].

Thus, neural crest cells migrate far more extensively than other fetal neural stem cells during development, form mesenchymal tissues, most of which develop from embryonic mesoderm as well as the components of the CNS and PNS which arises from embryonic ectoderm. This close link, in neural crest development, between ectodermally derived tissues and mesodermally derived tissues accounts in part for the interest in neural crest cells as a kind of stem cell. In fact, neural crest cells meet several criteria of stem cells. They can self-renew (at least in the fetus) and can differentiate into multiple cells types, which include cells derived from two of the three embryonic germ layers [76].

Recent studies indicate that neural crest cells persist late into gestation and can be isolated from E14.5 rat sciatic nerve, a peripheral nerve in the hindlimb. The cells incorporate BrdU, indicating that they are dividing in vivo. When transplanted into chick embryos, the rat neural crest cells develop into neurons and glia, an indication of their stem cell-like properties [67]. However, the ability of rat E14.5 neural crest cells taken from sciatic nerve to generate nerve and glial cells in chick is more limited than neural crest cells derived from younger, E10.5 rat embryos. At the earlier stage of development, the neural tube has formed, but neural crest cells have not yet migrated to their final destinations. Neural crest cells from early developmental stages are more sensitive to bone morphogenetic protein 2 (BMP2) signaling, which may help explain their greater differentiation potential [106].

The notion that the bone marrow contains stem cells is not new. One population of bone marrow cells, the hematopoietic stem cells (HSCs), is responsible for forming all of the types of blood cells in the body. HSCs were recognized as a stem cells more than 40 years ago [9, 99]. Bone marrow stromal cellsa mixed cell population that generates bone, cartilage, fat, fibrous connective tissue, and the reticular network that supports blood cell formationwere described shortly after the discovery of HSCs [30, 32, 73]. The mesenchymal stem cells of the bone marrow also give rise to these tissues, and may constitute the same population of cells as the bone marrow stromal cells [78]. Recently, a population of progenitor cells that differentiates into endothelial cells, a type of cell that lines the blood vessels, was isolated from circulating blood [8] and identified as originating in bone marrow [89]. Whether these endothelial progenitor cells, which resemble the angioblasts that give rise to blood vessels during embryonic development, represent a bona fide population of adult bone marrow stem cells remains uncertain. Thus, the bone marrow appears to contain three stem cell populationshematopoietic stem cells, stromal cells, and (possibly) endothelial progenitor cells (see Figure 4.3. Hematopoietic and Stromal Stem Cell Differentiation).

Figure 4.3. Hematopoietic and Stromal Stem Cell Differentiation.

( 2001 Terese Winslow, Lydia Kibiuk)

Two more apparent stem cell types have been reported in circulating blood, but have not been shown to originate from the bone marrow. One population, called pericytes, may be closely related to bone marrow stromal cells, although their origin remains elusive [12]. The second population of blood-born stem cells, which occur in four species of animals testedguinea pigs, mice, rabbits, and humansresemble stromal cells in that they can generate bone and fat [53].

Hematopoietic Stem Cells. Of all the cell types in the body, those that survive for the shortest period of time are blood cells and certain kinds of epithelial cells. For example, red blood cells (erythrocytes), which lack a nucleus, live for approximately 120 days in the bloodstream. The life of an animal literally depends on the ability of these and other blood cells to be replenished continuously. This replenishment process occurs largely in the bone marrow, where HSCs reside, divide, and differentiate into all the blood cell types. Both HSCs and differentiated blood cells cycle from the bone marrow to the blood and back again, under the influence of a barrage of secreted factors that regulate cell proliferation, differentiation, and migration (see Chapter 5. Hematopoietic Stem Cells).

HSCs can reconstitute the hematopoietic system of mice that have been subjected to lethal doses of radiation to destroy their own hematopoietic systems. This test, the rescue of lethally irradiated mice, has become a standard by which other candidate stem cells are measured because it shows, without question, that HSCs can regenerate an entire tissue systemin this case, the blood [9, 99]. HSCs were first proven to be blood-forming stem cells in a series of experiments in mice; similar blood-forming stem cells occur in humans. HSCs are defined by their ability to self-renew and to give rise to all the kinds of blood cells in the body. This means that a single HSC is capable of regenerating the entire hematopoietic system, although this has been demonstrated only a few times in mice [72].

Over the years, many combinations of surface markers have been used to identify, isolate, and purify HSCs derived from bone marrow and blood. Undifferentiated HSCs and hematopoietic progenitor cells express c-kit, CD34, and H-2K. These cells usually lack the lineage marker Lin, or express it at very low levels (Lin-/low). And for transplant purposes, cells that are CD34+ Thy1+ Lin- are most likely to contain stem cells and result in engraftment.

Two kinds of HSCs have been defined. Long-term HSCs proliferate for the lifetime of an animal. In young adult mice, an estimated 8 to 10 % of long-term HSCs enter the cell cycle and divide each day. Short-term HSCs proliferate for a limited time, possibly a few months. Long-term HSCs have high levels of telomerase activity. Telomerase is an enzyme that helps maintain the length of the ends of chromosomes, called telomeres, by adding on nucleotides. Active telomerase is a characteristic of undifferentiated, dividing cells and cancer cells. Differentiated, human somatic cells do not show telomerase activity. In adult humans, HSCs occur in the bone marrow, blood, liver, and spleen, but are extremely rare in any of these tissues. In mice, only 1 in 10,000 to 15,000 bone marrow cells is a long-term HSC [105].

Short-term HSCs differentiate into lymphoid and myeloid precursors, the two classes of precursors for the two major lineages of blood cells. Lymphoid precursors differentiate into T cells, B cells, and natural killer cells. The mechanisms and pathways that lead to their differentiation are still being investigated [1, 2]. Myeloid precursors differentiate into monocytes and macrophages, neutrophils, eosinophils, basophils, megakaryocytes, and erythrocytes [3]. In vivo, bone marrow HSCs differentiate into mature, specialized blood cells that cycle constantly from the bone marrow to the blood, and back to the bone marrow [26]. A recent study showed that short-term HSCs are a heterogeneous population that differ significantly in terms of their ability to self-renew and repopulate the hematopoietic system [42].

Attempts to induce HSC to proliferate in vitroon many substrates, including those intended to mimic conditions in the stromahave frustrated scientists for many years. Although HSCs proliferate readily in vivo, they usually differentiate or die in vitro [26]. Thus, much of the research on HSCs has been focused on understanding the factors, cell-cell interactions, and cell-matrix interactions that control their proliferation and differentiation in vivo, with the hope that similar conditions could be replicated in vitro. Many of the soluble factors that regulate HSC differentiation in vivo are cytokines, which are made by different cell types and are then concentrated in the bone marrow by the extracellular matrix of stromal cellsthe sites of blood formation [45, 107]. Two of the most-studied cytokines are granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) [40, 81].

Also important to HSC proliferation and differentiation are interactions of the cells with adhesion molecules in the extracellular matrix of the bone marrow stroma [83, 101, 110].

Bone Marrow Stromal Cells. Bone marrow (BM) stromal cells have long been recognized for playing an important role in the differentiation of mature blood cells from HSCs (see Figure 4.3. Hematopoietic and Stromal Stem Cell Differentiation). But stromal cells also have other important functions [30, 31]. In addition to providing the physical environment in which HSCs differentiate, BM stromal cells generate cartilage, bone, and fat. Whether stromal cells are best classified as stem cells or progenitor cells for these tissues is still in question. There is also a question as to whether BM stromal cells and so-called mesenchymal stem cells are the same population [78].

BM stromal cells have many features that distinguish them from HSCs. The two cell types are easy to separate in vitro. When bone marrow is dissociated, and the mixture of cells it contains is plated at low density, the stromal cells adhere to the surface of the culture dish, and the HSCs do not. Given specific in vitro conditions, BM stromal cells form colonies from a single cell called the colony forming unit-F (CFU-F). These colonies may then differentiate as adipocytes or myelosupportive stroma, a clonal assay that indicates the stem cell-like nature of stromal cells. Unlike HSCs, which do not divide in vitro (or proliferate only to a limited extent), BM stromal cells can proliferate for up to 35 population doublings in vitro [16]. They grow rapidly under the influence of such mitogens as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and insulin-like growth factor-1 (IGF-1) [12].

To date, it has not been possible to isolate a population of pure stromal cells from bone marrow. Panels of markers used to identify the cells include receptors for certain cytokines (interleukin-1, 3, 4, 6, and 7) receptors for proteins in the extracellular matrix, (ICAM-1 and 2, VCAM-1, the alpha-1, 2, and 3 integrins, and the beta-1, 2, 3 and 4 integrins), etc. [64]. Despite the use of these markers and another stromal cell marker called Stro-1, the origin and specific identity of stromal cells have remained elusive. Like HSCs, BM stromal cells arise from embryonic mesoderm during development, although no specific precursor or stem cell for stromal cells has been isolated and identified. One theory about their origin is that a common kind of progenitor cellperhaps a primordial endothelial cell that lines embryonic blood vesselsgives rise to both HSCs and to mesodermal precursors. The latter may then differentiate into myogenic precursors (the satellite cells that are thought to function as stem cells in skeletal muscle), and the BM stromal cells [10].

In vivo, the differentiation of stromal cells into fat and bone is not straightforward. Bone marrow adipocytes and myelosupportive stromal cellsboth of which are derived from BM stromal cellsmay be regarded as interchangeable phenotypes [10, 11]. Adipocytes do not develop until postnatal life, as the bones enlarge and the marrow space increases to accommodate enhanced hematopoiesis. When the skeleton stops growing, and the mass of HSCs decreases in a normal, age-dependent fashion, BM stromal cells differentiate into adipocytes, which fill the extra space. New bone formation is obviously greater during skeletal growth, although bone "turns over" throughout life. Bone forming cells are osteoblasts, but their relationship to BM stromal cells is not clear. New trabecular bone, which is the inner region of bone next to the marrow, could logically develop from the action of BM stromal cells. But the outside surface of bone also turns over, as does bone next to the Haversian system (small canals that form concentric rings within bone). And neither of these surfaces is in contact with BM stromal cells [10, 11].

It is often difficultif not impossibleto distinguish adult, tissue-specific stem cells from progenitor cells. With that caveat in mind, the following summary identifies reports of stem cells in various adult tissues.

Endothelial Progenitor Cells. Endothelial cells line the inner surfaces of blood vessels throughout the body, and it has been difficult to identify specific endothelial stem cells in either the embryonic or the adult mammal. During embryonic development, just after gastrulation, a kind of cell called the hemangioblast, which is derived from mesoderm, is presumed to be the precursor of both the hematopoietic and endothelial cell lineages. The embryonic vasculature formed at this stage is transient and consists of blood islands in the yolk sac. But hemangioblasts, per se, have not been isolated from the embryo and their existence remains in question. The process of forming new blood vessels in the embryo is called vasculogenesis. In the adult, the process of forming blood vessels from pre-existing blood vessels is called angiogenesis [50].

Evidence that hemangioblasts do exist comes from studies of mouse embryonic stem cells that are directed to differentiate in vitro. These studies have shown that a precursor cell derived from mouse ES cells that express Flk-1 [the receptor for vascular endothelial growth factor (VEGF) in mice] can give rise to both blood cells and blood vessel cells [88, 109]. Both VEGF and fibroblast growth factor-2 (FGF-2) play critical roles in endothelial cell differentiation in vivo [79].

Several recent reports indicate that the bone marrow contains cells that can give rise to new blood vessels in tissues that are ischemic (damaged due to the deprivation of blood and oxygen) [8, 29, 49, 94]. But it is unclear from these studies what cell type(s) in the bone marrow induced angiogenesis. In a study which sought to address that question, researchers found that adult human bone marrow contains cells that resemble embryonic hemangioblasts, and may therefore be called endothelial stem cells.

In more recent experiments, human bone marrow-derived cells were injected into the tail veins of rats with induced cardiac ischemia. The human cells migrated to the rat heart where they generated new blood vessels in the infarcted muscle (a process akin to vasculogenesis), and also induced angiogenesis. The candidate endothelial stem cells are CD34+(a marker for HSCs), and they express the transcription factor GATA-2 [51]. A similar study using transgenic mice that express the gene for enhanced green fluorescent protein (which allows the cells to be tracked), showed that bone-marrow-derived cells could repopulate an area of infarcted heart muscle in mice, and generate not only blood vessels, but also cardiomyocytes that integrated into the host tissue [71] (see Chapter 9. Can Stem Cells Repair a Damaged Heart?).

And, in a series of experiments in adult mammals, progenitor endothelial cells were isolated from peripheral blood (of mice and humans) by using antibodies against CD34 and Flk-1, the receptor for VEGF. The cells were mononuclear blood cells (meaning they have a nucleus) and are referred to as MBCD34+ cells and MBFlk1+ cells. When plated in tissue-culture dishes, the cells attached to the substrate, became spindle-shaped, and formed tube-like structures that resemble blood vessels. When transplanted into mice of the same species (autologous transplants) with induced ischemia in one limb, the MBCD34+ cells promoted the formation of new blood vessels [8]. Although the adult MBCD34+ and MBFlk1+ cells function in some ways like stem cells, they are usually regarded as progenitor cells.

Skeletal Muscle Stem Cells. Skeletal muscle, like the cardiac muscle of the heart and the smooth muscle in the walls of blood vessels, the digestive system, and the respiratory system, is derived from embryonic mesoderm. To date, at least three populations of skeletal muscle stem cells have been identified: satellite cells, cells in the wall of the dorsal aorta, and so-called "side population" cells.

Satellite cells in skeletal muscle were identified 40 years ago in frogs by electron microscopy [62], and thereafter in mammals [84]. Satellite cells occur on the surface of the basal lamina of a mature muscle cell, or myofiber. In adult mammals, satellite cells mediate muscle growth [85]. Although satellite cells are normally non-dividing, they can be triggered to proliferate as a result of injury, or weight-bearing exercise. Under either of these circumstances, muscle satellite cells give rise to myogenic precursor cells, which then differentiate into the myofibrils that typify skeletal muscle. A group of transcription factors called myogenic regulatory factors (MRFs) play important roles in these differentiation events. The so-called primary MRFs, MyoD and Myf5, help regulate myoblast formation during embryogenesis. The secondary MRFs, myogenin and MRF4, regulate the terminal differentiation of myofibrils [86].

With regard to satellite cells, scientists have been addressing two questions. Are skeletal muscle satellite cells true adult stem cells or are they instead precursor cells? Are satellite cells the only cell type that can regenerate skeletal muscle. For example, a recent report indicates that muscle stem cells may also occur in the dorsal aorta of mouse embryos, and constitute a cell type that gives rise both to muscle satellite cells and endothelial cells. Whether the dorsal aorta cells meet the criteria of a self-renewing muscle stem cell is a matter of debate [21].

Another report indicates that a different kind of stem cell, called an SP cell, can also regenerate skeletal muscle may be present in muscle and bone marrow. SP stands for a side population of cells that can be separated by fluorescence-activated cell sorting analysis. Intravenously injecting these muscle-derived stem cells restored the expression of dystrophin in mdx mice. Dystrophin is the protein that is defective in people with Duchenne's muscular dystrophy; mdx mice provide a model for the human disease. Dystrophin expression in the SP cell-treated mice was lower than would be needed for clinical benefit. Injection of bone marrow- or muscle-derived SP cells into the dystrophic muscle of the mice yielded equivocal results that the transplanted cells had integrated into the host tissue. The authors conclude that a similar population of SP stem cells can be derived from either adult mouse bone marrow or skeletal muscle, and suggest "there may be some direct relationship between bone marrow-derived stem cells and other tissue- or organ-specific cells" [43]. Thus, stem cell or progenitor cell types from various mesodermally-derived tissues may be able to generate skeletal muscle.

Epithelial Cell Precursors in the Skin and Digestive System. Epithelial cells, which constitute 60 percent of the differentiated cells in the body are responsible for covering the internal and external surfaces of the body, including the lining of vessels and other cavities. The epithelial cells in skin and the digestive tract are replaced constantly. Other epithelial cell populationsin the ducts of the liver or pancreas, for exampleturn over more slowly. The cell population that renews the epithelium of the small intestine occurs in the intestinal crypts, deep invaginations in the lining of the gut. The crypt cells are often regarded as stem cells; one of them can give rise to an organized cluster of cells called a structural-proliferative unit [93].

The skin of mammals contains at least three populations of epithelial cells: epidermal cells, hair follicle cells, and glandular epithelial cells, such as those that make up the sweat glands. The replacement patterns for epithelial cells in these three compartments differ, and in all the compartments, a stem cell population has been postulated. For example, stem cells in the bulge region of the hair follicle appear to give rise to multiple cell types. Their progeny can migrate down to the base of the follicle where they become matrix cells, which may then give rise to different cell types in the hair follicle, of which there are seven [39]. The bulge stem cells of the follicle may also give rise to the epidermis of the skin [95].

Another population of stem cells in skin occurs in the basal layer of the epidermis. These stem cells proliferate in the basal region, and then differentiate as they move toward the outer surface of the skin. The keratinocytes in the outermost layer lack nuclei and act as a protective barrier. A dividing skin stem cell can divide asymmetrically to produce two kinds of daughter cells. One is another self-renewing stem cell. The second kind of daughter cell is an intermediate precursor cell which is then committed to replicate a few times before differentiating into keratinocytes. Self-renewing stem cells can be distinguished from this intermediate precusor cell by their higher level of 1 integrin expression, which signals keratinocytes to proliferate via a mitogen-activated protein (MAP) kinase [112]. Other signaling pathways include that triggered by -catenin, which helps maintain the stem-cell state [111], and the pathway regulated by the oncoprotein c-Myc, which triggers stem cells to give rise to transit amplifying cells [36].

Stem Cells in the Pancreas and Liver. The status of stem cells in the adult pancreas and liver is unclear. During embryonic development, both tissues arise from endoderm. A recent study indicates that a single precursor cell derived from embryonic endoderm may generate both the ventral pancreas and the liver [23]. In adult mammals, however, both the pancreas and the liver contain multiple kinds of differentiated cells that may be repopulated or regenerated by multiple types of stem cells. In the pancreas, endocrine (hormone-producing) cells occur in the islets of Langerhans. They include the beta cells (which produce insulin), the alpha cells (which secrete glucagon), and cells that release the peptide hormones somatostatin and pancreatic polypeptide. Stem cells in the adult pancreas are postulated to occur in the pancreatic ducts or in the islets themselves. Several recent reports indicate that stem cells that express nestinwhich is usually regarded as a marker of neural stem cellscan generate all of the cell types in the islets [60, 113] (see Chapter 7. Stem Cells and Diabetes).

The identity of stem cells that can repopulate the liver of adult mammals is also in question. Recent studies in rodents indicate that HSCs (derived from mesoderm) may be able to home to liver after it is damaged, and demonstrate plasticity in becoming into hepatocytes (usually derived from endoderm) [54, 77, 97]. But the question remains as to whether cells from the bone marrow normally generate hepatocytes in vivo. It is not known whether this kind of plasticity occurs without severe damage to the liver or whether HSCs from the bone marrow generate oval cells of the liver [18]. Although hepatic oval cells exist in the liver, it is not clear whether they actually generate new hepatocytes [87, 98]. Oval cells may arise from the portal tracts in liver and may give rise to either hepatocytes [19, 55] and to the epithelium of the bile ducts [37, 92]. Indeed, hepatocytes themselves, may be responsible for the well-know regenerative capacity of liver.

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Cardiac Stem Cells Comments Off on 4. The Adult Stem Cell | stemcells.nih.gov | January 14th, 2020

German racing driver, Formula 1 Michael Schumacher was hospitalized in one of medical institutions of Paris for the holding of special procedures, namely therapy using stem cells. According to the wife of a holder of numerous records, her husband decided not to disseminate information about their own health, but the woman said that the former athlete is in good hands.

In early autumn last year Michael Schumacher was taken to Hopital Europeen Georges Pompidou, located in Paris, it was said that seven-time world champion was conscious. The athlete was placed in the division of cardiovascular surgery, and to fight for the health of Schumacher took 69-year-old Professor and renowned cardiac surgeon Phillip Menashe, the first at the time transplantiversary patients muscle stem cells from human myocardial infarction.

According to preliminary reports, Schumacher is in the hospital plan to treat the nervous system, but doctors doubt the effectiveness of stem cell therapy to regenerate its functioning. While these experiments have not brought positive results over the last thirty years, writes the Express.

Natasha Kumar is a general assignment reporter at the Times Hub. She has covered sports, entertainment and many other beats in her journalism career, and has lived in Manhattan for more than 8 years. Natasha has appeared periodically on national television shows and has been published in (among others) Hindustan Times.? Times of India

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Cardiac Stem Cells Comments Off on Michael Schumacher will be treated in Paris with stem cells – The Times Hub | January 14th, 2020