HOUSTON--(BUSINESS WIRE)-- Kiromic BioPharma, Inc. (Nasdaq: KRBP)

Expansion of in-house cGMP manufacturing facility to provide support to the Company's clinical trials. Therapeutic doses expected to be ready for first in-human dosing in 3Q-2021.

Mr. Ignacio Nez, a 20-year industry veteran in global operations and manufacturing, is joining the Kiromic team to take the company to the next level and to scale up cGMP manufacturing capabilities internally.

Kiromic is an immuno-oncology company using Artificial Intelligence (AI) to identify critical markers in solid tumors to develop Allogeneic CAR-T cell therapy.

Kiromics CAR-T technology addresses critical efficacy and safety issues by developing switches to control T-cell activity reducing cell exhaustion and cytokine release syndrome among others.

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Expansion of in-house cGMP manufacturing facility

In support of the upcoming INDs, Kiromic is expanding its HQ in Houston, TX. To their current cGMP, R&D labs, vivarium and offices, Kiromic is adding an adjacent space where more cGMP clean rooms, QC, QA and regulatory, offices and ultra-cold storage will have place.

This new expansion will add up to a total of approximately 30,000 square feet and will enable supporting Kiromic significant growth as the company approaches the clinical phase.

Appointment of Chief Operating and Manufacturing Officer

Mr. Ignacio Nez MSCHE, MBB has been appointed as Chief Operating Officer and Manufacturing Officer.

Mr. Nez will play a key role in expanding the scale up of Kiromics operations, including manufacturing, taking the company from pre-IND status to the clinical phase and eventually to commercial phase.

Mr. Nez has over 20 years of global experience in corporate functions including manufacturing, research, operational excellence and strategy. He has held senior leadership positions in companies including General Electric, Johnson & Johnson and Novartis. Most recently, he was the Executive Director of Manufacturing at the Gene Therapy Program of the University of Pennsylvania.

Before that, he was the Head of Manufacturing Strategy and Operations Excellence at Novartis, where he was charged with transforming manufacturing operations in support of the ramp up of Kymriah, the first FDA-approved CAR-T cell therapy, which was developed at the University of Pennsylvania.

Mr. Nez holds an MSC in Chemical Engineering from the University of Granada.

CEO of Kiromic, Maurizio Chiriva-Internati, DBSc, PhDs

Kiromic believes it has the key to resolve the current challenges in cell therapy and I believe we will become the reference and lead the industry going forward.

Cell Therapy Manufacturing: Autologous (patient) vs. Allogeneic (healthy donor)

The table below outlines the current cell therapy manufacturing challenges which Kiromic allogeneic cell manufacturing expects to resolve and which Mr. Nez will advance.

CAR-T technology challenges

AutologousCAR-T

KiromicAllogeneic

CAR-T

Safety

CRS

(cytokine release syndrome)

-

+

CRES

(T-cell related encephalopathy syndrome)

-

+

Efficacy

Efficacy

++

++++ (*)

Indication

BloodCancers

SolidTumors

T-cell overstimulation

-

+

T-cell exhaustion

-

+

Tumor immune suppressive microenvironment

-

+

Tumor specific antigens (shedding)

CD19

multipletargets

Manufacturing

Patients variation & manufacturing success

-

+

Lead time(autologous vs. off-the-shelf)

17-30 days

None

Cost of Manufacturing (per patient)

++++

+

Application

Order of treatment application

3rd Line

TBD

Treatment Setting

24 Daysin-patient

24 hoursin-patient (**)

(*) based upon Kiromic's pre-clinical projections, AACR posters (**) as filed in IND to the FDA (May 2021).

COMO of Kiromic, Mr. Ignacio Nez stated:

"I am impressed by Kiromics end-to-end approach to cell therapy as I believe they address almost every known issue in current cell therapies.

Expanded Kiromic in-house manufacturing capabilities are capital efficient and are optimized to deliver the capacity projections, making manufacturing a competitive advantage and not a challenge for the company.

I believe that this technology is meant to change the cell and gene therapy landscape, reshaping the future approach to cancer treatment.

I am humbled to join the team at this critical juncture."

CMO of Kiromic, Scott Dahlbeck, MD, PharmD stated:

Kiromic is pleased to obtain the clinical manufacturing expertise of Mr. Nez, whose expertise and biopharmaceutical background I believe will serve to capitalize on the cellular therapy production capabilities of Kiromic, leading to a new era in immuno-oncology treatments for solid tumors."

CSIO of Kiromic, Mr. Gianluca Rotino stated:

"I believe all of our cell therapy manufacturing is novel and resolves key industry challenges.

It is my opinion, that our manufacturing technology will be very much sought after by pharma companies and cell therapy industry players.

Our cell therapy IPs portfolio is very strong.

This manufacturing expansion and bringing Mr. Nunez to Kiromic are strategically important milestones that makes us ready to face the challenges of the clinical trials and puts us on the path of commercial viability of our novel therapy."

CFO of Kiromic, Mr. Tony Tontat stated:

"Capital efficiency is what we strove to deliver with our investments as we were building out our cGMP facility.

We are happy to receive this additional validation of capital efficiency from an industry veteran like Mr. Nez."

How Our KB-PD1 Live Cell Therapy CAR-T Improves CAR-T Market:

Marketed andtraditional CAR-T

Kiromic KB-PD1

Malignancies(Cancer Type)

Hematologic

Solid Tumors

Live Cell Origin

Autologous

Live Cells from

pre-treatment patients

Allogeneic

Live Cells from

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Kiromic Announces Expansion of In-House Cell therapy cGMP Manufacturing Facility and the Appointment of Industry Veteran Ignacio Nez as Chief...

IPS Cell Therapy Comments Off on Kiromic Announces Expansion of In-House Cell therapy cGMP Manufacturing Facility and the Appointment of Industry Veteran Ignacio Nez as Chief… | June 8th, 2021

AMSBIO reports upon a publication** that cites how its STEM-CELLBANKER animal-free cryopreservation media has played a role in the development of a cell therapy for Parkinsons Disease that will soon be going into clinical trials.

Parkinsons disease is one of the most common neurodegenerative diseases worldwide. Its main features include motor symptoms such as bradykinesia, rigidity, resting tremor, and postural instability, though non-motor symptoms are often also present. Currently the main therapy for Parkinsons disease consists of augmentation of dopamine levels in the brain via dopamine supplements or agonists or by inhibiting dopamine degradation. Treatment using this methodology is symptomatic but not long-lasting, and unfortunately has no neuroprotective effect. Cell therapy with grafts of human fetal tissue from the ventral mesencephalon have been carried out successfully, with multiple reports of long-term benefits.

A pioneering study from the Centre for Stem Cell Biology at the Memorial Sloan Kettering Cancer Centre (USA) has focused on developing stem cell-derived midbrain dopamine progenitors for the treatment of Parkinsons Disease. This study highlighted, amongst other things, that scientists have been able to demonstrate the efficacy of STEM-CELLBANKER to store, thaw and then recover these manufactured cells for clinical use in patients.

STEM-CELLBANKER is a ready-to-use, chemically defined, animal-free freezing medium manufactured under GMP conditions. It is optimized for embryonic stem (ES) and induced pluripotent stem (iPS) cell storage, as well as being a suitable solution for the cryopreservation of other fragile cell types. Containing only European or US Pharmacopoeia graded ingredients, STEM-CELLBANKER is the optimal choice for storage of cells developed for cell therapy applications. It is also available as a DMSO free formulation. STEM-CELLBANKER significantly increases cell viability while maintaining cell pluripotency, normal karyotype and proliferation ability after freeze-thaw. STEM-CELLBANKER is ready-to-use and requires no special devices, such as a controlled rate freezer, in order to achieve consistently high viabilities following resuscitation from cryopreservation, even over extended long-term storage.

To read the Parkinsons Disease cell therapy paper in full please visithttps://bit.ly/3eYwZ5L. For further information including a video introduction to STEM-CELLBANKER please visithttps://www.amsbio.com/stem-cell-cryopreservation/or contact AMSBIO on +44-1235-828200 / +1-617-945-5033 /info@amsbio.com.

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Cryopreservation Media helps in Development of a Cell Therapy for Parkinson's Disease - Microbioz India

IPS Cell Therapy Comments Off on Cryopreservation Media helps in Development of a Cell Therapy for Parkinson’s Disease – Microbioz India | June 8th, 2021

CARLSBAD, Calif.--(BUSINESS WIRE)--Accelerated Biosciences, a regenerative medicine innovator, announced today new data that further demonstrates statistically significant cytolysis with induced pluripotent stem cell (iPSC)-derived natural killer (NK) cells programmed from its ethically sourced human trophoblast stem cells (hTSCs). Pluristyx, a Seattle-based firm supporting drug development, regenerative medicine, and cell and gene therapies, further confirmed Accelerated Biosciences hTSC line offers before-unrealized opportunities in cell-specific therapeutics. Along with this recent data on successful iPSC differentiation, Accelerated Biosciences has already demonstrated efficient differentiation of its pluripotent stem cells with remarkable doubling times and growth characteristics to programmed NK, cartilage, bone, fat, neuron, pancreas, liver, and secretome cells.

This new data validates our findings, explains Yuta Lee, President and Founder of Accelerated Biosciences. We know the properties of our trophoblast stem cells have been long-sought by the medical science community because of the potential to speed and amplify the development of life-saving therapeutics; theyre immune privileged, chromosomally stable (not tumorigenic), pathogen free, pluripotent, easy to scale and manufacturer, and of special interest, they are ethically sourced from the chorionic villi (pre-placental tissue) of non-viable and often life-threatening tubal ectopic pregnancies. Mr. Lees father, Professor Jau-Nan Lee, MB, MD, PhD, an obstetrics and gynecologic physician and researcher in Taiwan, first isolated hTSC in 2003. Mr. Lee created Accelerated Biosciences to elevate the visibility of this pluripotent human trophoblast stem cell platform to those engaged in developing allogeneic cell therapeutics and has been instrumental in the filing and prosecution of intellectual property to protect the companys hTSC platform to date holding 34 patents.

Benjamin Fryer, PhD, Co-founder and CEO of Pluristyx, worked closely with Accelerated Biosciences to prepare much of its key hTSC data. Dr. Fryer, a trophoblast expert who was previously a research scientist at Janssen Research & Development of Johnson & Johnson, now serves on Accelerated Biosciences Scientific Advisory Board. Initially I was skeptical these cells were what they said they were. If we hadnt grown and characterized them in our lab, I might have remained skeptical. These are indeed trophoblast stem cells, explained Dr. Fryer. The potential of these cells is enormous. One of the industrys largest challenges is that its almost impossible to scale primary cells. These cells are scalable. With these cells you can make the amount required for millions of patients and theyre sourced compliant to regulatory requirements. Weve made IPS cells (induced pluripotent stem cells) and NK (natural killer) cells from them, which is the next wave of cells for cell therapies. For therapeutic developers, because these cells are not sourced from a person or viable embryo, these cells deliver the trifecta of legal, ethical, and IP advantages.

As the biotechnology industry works toward developing therapies that target only diseased cells without harming healthy cells and tissues, cell-based therapies draw increasing interest, explains industry expert, Martina Molsbergen, CEO of C14 Consulting, who has partnered with Accelerated Biosciences in a business development role. With all the promise that cell therapies hold, the biotechnology industry also remains concerned that the therapeutics are derived in a socially and ethically responsible manner. Accelerated Biosciences has discovered and is now offering what scientists see as the holy grail of stem cell sources.

Prominent biosciences experts have been drawn to Accelerated Biosciences cell breakthrough. Protein chemist and molecular biologist Igor Fisch, PhD, former President and CEO of Selexis, Geneva, Switzerland, recognizes the impact that Accelerated Biosciences hTSCs will have on human health: Not only are these cells politically correct, but they can also differentiate. Because they are sourced from pre-placenta material, theyre immune privileged, which means that are not seen as foreign by the human body. With these cells, we can create a cell bank a single source for a wide range of patients.

Peter Hudson, FTSE, BSc Hons, PhD, Chief Scientist and a senior advisor to Avipep P/L in Melbourne, Australia, and an adjunct professor at the University of Queensland, led a large oncology consortium to complete the first Phase 1 clinical trial of a novel engineered antibody targeting prostate and ovarian cancer. Hudsons interest in Accelerated Biosciences hTSCs has evolved into a role on its Scientific Advisory Board. Trophoblast stem cells are likely to be the next wave of cancer-targeting therapeutics, explains Dr. Hudson. The ability to ethically source trophoblast stem cells and program them to target only diseased, cancerous cells is very powerful technology.

Why are scientists so interested in stem cell-based therapies?

The human body constantly produces specialized cells from its own stem cells (undifferentiated cells) to renew and repair itself. Current therapies harness this power in autologous cell therapies in which the patients own cells are removed, differentiated into disease-fighting cells, and reinserted.

What makes the human trophoblast stem cell so important to medical science?

The human trophoblast stem cell (hTSC) comes from placental tissue and has special properties that make it extremely desirable to therapeutic developers. The hTSC is such an early stem cell that it has much more capacity for growth than a stem cell taken from an adult, for example. This means that one cell can become millions. The hTSC also carries with it the same immune-privilege that a growing embryo has inside its mother: its not seen as foreign although its genetically different than its mother. Unlike other foreign materials, the hTSC is not rejected by the human body, which means that it can be used with many different patients (allogeneic cell therapy). With these benefits, the scientific community holds a high regard for hTSCs, but it also faces socio-ethical concerns about how those stem cells are typically sourced.

Accelerated Biosciences sidesteps hTSC sourcing concerns in a profoundly elegant way. Dr. Jau-Nan Lee, an OB-GYN in Taiwan, found inspiration in what was considered medical waste. When surgical intervention was necessary to remove an ectopic pregnancy that would otherwise risk the womans life, the non-viable embryo and pre-placental tissue lodged in the fallopian tube was removed, sent to pathology, and discarded. Gaining permission from institutional colleagues and sampling the pre-placental tissue, Dr. Lee isolated hTSC that offered all the benefits of hTSC pluripotency, immune privilege, and scalability without pathogens and without ethical compromises.

About Accelerated Biosciences

Founded in 2013, Accelerated Biosciences is a private company focused on regenerative medicine and built around the hTSC discoveries of obstetrics and gynecology physician and researcher, Professor Jau-Nan Lee, MB, MD, PhD. Accelerated Biosciences holds a large and robust patent portfolio and an encumbrance-free intellectual property (IP) estate. Accelerated Biosciences mission is to leverage its renewable, immune-privileged human cell source to fuel breakthrough cell therapies that effectively target the most challenging diseases of the human body. For more information about Accelerated Biosciences, visit acceleratedbio.com or email mmolsbergen@c14consultinggroup.com.

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Accelerated Biosciences' Immune-Privileged Human Trophoblast Stem Cells (hTSCs) Offer Breakthrough Opportunities in Cancer-Targeting Therapeutics and...

IPS Cell Therapy Comments Off on Accelerated Biosciences’ Immune-Privileged Human Trophoblast Stem Cells (hTSCs) Offer Breakthrough Opportunities in Cancer-Targeting Therapeutics and… | May 15th, 2021

Factor reveals advances in mRNA, circleRNA, gene editing, cell reprogramming, and iPS cell-derived NK-cell technologies.

Digital presentations will be made available on the ASGCT website on May 11, 2021. For more information on the upcoming American Society of Genetic & Cell Therapy (ASGCT) Annual Meeting, visit https://annualmeeting.asgct.org/

About Factor BioscienceFounded in 2011, Factor Bioscience develops technologies for engineering cells to advance the study and treatment of disease. Factor collaborates with academic and industrial partners to develop therapeutic products based on its mRNA, gene editing, cell reprogramming, and nucleic-acid delivery technologies. Factor Bioscience is privately held and is headquartered in Cambridge, Massachusetts. For more information, visit http://www.factorbio.com.

Media Contact:

Allen Mireles[emailprotected]

Related Linkshttp://www.factorbio.comhttps://annualmeeting.asgct.org/

SOURCE Factor Bioscience Inc.

http://www.factorbio.com

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Factor Bioscience to Deliver Six Digital Presentations at the American Society of Gene & Cell Therapy (ASGCT) 24th Annual Meeting - PRNewswire

IPS Cell Therapy Comments Off on Factor Bioscience to Deliver Six Digital Presentations at the American Society of Gene & Cell Therapy (ASGCT) 24th Annual Meeting – PRNewswire | May 15th, 2021

Small dreams have no power to move hearts, and in a new six-year strategic plan, St. Jude Childrens Research Hospital is thinking very big.

What would it take to drastically increase cure rates for childhood cancer worldwide?

St. Judes answer: $11.5 billion and an additional 1,400 jobs.

To get a rough sense of scale, work it out with a pencil:

Spread over six yearsat $1.916 billion each yearits just under a third of the NCIs annual spend, fourfold this years projected revenues of the American Cancer Society, and more than seventyfold the budget of the World Health Organizations International Agency for Research on Cancer.

Its a broad and ambitious plan that will allow the institution to grow at an almost 8% compound annual growth rate, James Downing, president and CEO of St. Jude, said to The Cancer Letter.

At a global level, we also want to see identifiable increases in cure rates. We are watching those very carefully. Our goal is to move toward cure rates of 60% for diseases like acute lymphoblastic leukemia, Hodgkins lymphoma and Wilms tumor, Downing said. As we look at a global population, survival rates hover around 20%, and wed like to see those go up year by year.

A lot of our efforts are based on implementation science, looking at what works and what doesnt work. Workforce, drug distribution and true advancements in cure rates are what were seeking over the next six years.

The plan, rolled out on April 27, calls for an acceleration of research and treatment globallynot just for pediatric cancer, but also other illnesses, including blood disorders, neurological diseases, and infectious diseases.

Not surprisingly, this amount represents the largest investment the Memphis, Tenn. hospital has made in its nearly 60-year history. The previous strategic plan, the largest expansion in the institutions history, resulted in $7 billion in investments (The Cancer Letter, May 19, 2017).

The multi-phase expansion plan is funded almost entirely by steadily increasing donor contributions generated by ALSAC, the fundraising and awareness organization for St. Jude.

It is an ambitious plan. But were going to have lots of new personnel, new investments, new technology and new partnerships. We have formal partnerships with many U.N. associate agencies and organizations around the world.

Within the past six years, St. Jude has advanced fundamental, clinical, and translational research, Downing said.

Two years ago, we began strategically looking at the most pressing issues in the field of pediatric cancer, Downing said. As we developed the strategic plan over those two years, there were many ideas we critically assessed, and we often said, Its not really best for St. Jude to pursue that.

In the end, we aligned on goals that collectively bring the prospect of remarkable benefits to the field of childhood cancer, and to children with cancer everywhere.

On campus, St. Jude accepted nearly 20% more new cancer patients; increased faculty by 30% and staff by 23%; and embarked on several large-scale construction projects.

The new strategic plan focuses on five areas: fundamental science, childhood cancer, pediatric catastrophic diseases, global impact, and workforce and workplace culture.

Were coming out of a six-year strategic plan in which we increased our number of cancer patients by 20%, with 30% new faculty, 23% more staff, many large-scale construction projects, said Charles Roberts, executive vice president of St. Jude and director of the hospitals Comprehensive Cancer Center. And were now going into a new strategic plan that is 60% larger than our prior plan.

Under the plan, St. Jude will hire nearly 70 new faculty members, plus supporting laboratory staff, to work in basic, translational, and clinical research across 22 departments.

These investigators will have the freedom to pursue the type of conceptually driven research that leads to tomorrows clinical advances.

As we launch a strategic plan, weve identified the most exciting opportunities and challenges at that point in time, Roberts said to The Cancer Letter. However, we fully realize that we dont know whats coming next. New discoveries will be made, and new opportunities will emerge. Via the blue-sky process, weve set aside substantial funds every year to invest in the pursuit of emerging opportunities suggested by faculty and staff.

Part of what brought me here from Boston was the last strategic plan, and its so exciting to be a part of this. But just looking at the numbers, 1,400 new positions, average salary of $90,000. Six hundred and forty of those positions are in research, 266 are in clinical, 100 are in global pediatric medicine, and 394 in support.

Those are the kinds of numbers that you need to make these things real, and I think its exciting for St. Jude and for the field of cancer research, as we bring in all of these new folks.

During the next six years, St. Jude will invest more than $250 million to expand technology and resources available to scientists and clinicians in their search to understand why pediatric catastrophic diseases arise, spread and resist treatments. These investments will include:

St. Jude will invest $3.7 billion during the next six years to expand cancer-focused research and related clinical care. These efforts will center on raising survival rates for the highest-risk cancers and for children with relapsed diseases, while simultaneously improving quality of life for pediatric cancer survivors. The investments will include:

In the U.S., more than 80% of children diagnosed with cancer will be cured. In contrast, 80% of children with cancer live in limited-resource countries, where a mere 20% survive their disease. To address this, St. Jude will more than triple its investment in its international efforts coordinated through St. Jude Global and the St. Jude Global Alliance during the next six years.

This represents an investment of more than $470 million. Global initiatives include:

Under the plan, St. Jude will expand research and treatment programs to advance cures for childhood catastrophic diseases. The $1.1 billion, six-year investment includes work in nonmalignant hematological diseases, such as sickle cell disease; a new laboratory-based research program in infectious diseases that affect children worldwide; and a new research and clinical program to better understand and treat pediatric neurological diseases.

The plan outlines several strategies to encourage teamwork, and internal and external collaboration. These will include:

It is estimated that 87% of funds to sustain and grow St. Jude over the next six years will come from public donations.

Patients at St. Jude do not receive a bill for treatment, travel, housing or fooda model established by ALSAC and St. Jude founder Danny Thomas, who believed in equal access to medical care and driving research advances.

There are an incredible number of donors across the United States who support St. Jude, Downing said. This carries a great responsibility for us to seek the maximum possible impact to improve outcomes for childhood cancer.

Downing and Roberts spoke with Matthew Ong, associate editor of The Cancer Letter.

Matthew Ong: Congratulations on the official launch of St. Judes second six-year strategic plan. Could you briefly walk us through whats in it?

James Downing: It is an exciting time for St. Jude Childrens Research Hospital. Were finishing our prior six-year strategic plan, which started in Fiscal Year 2016. That $7 billion investment in the organization spanned fundamental science, clinical and translational research, clinical operations, and our global efforts. During the course of the plan, we increased faculty by 30% and staff by 23% and accelerated progress against pediatric catastrophic diseases.

About two years ago, we started discussing the next strategic plan. We looked critically at what we had accomplished under the previous plan, the expertise we had assembled, and the major problems in the field of pediatric catastrophic diseases, including cancer, infectious diseases, nonmalignant hematologic diseases and pediatric neurologic diseases. During that period, we involved more than 200 individuals across the institution to develop the new strategic plan.

This plan, at its core, focuses on accelerating progress against pediatric catastrophic diseases on a global scale. It outlines a $11.5 billion investment during the next six years, which includes the addition of 1,400 jobs and $1.9 billion in new capital investments, construction and renovations. Its a broad and ambitious plan that will allow the institution to grow at an almost 8% compound annual growth rate.

The plan has 11 goals, divided among five major areas: fundamental science, pediatric cancer, other childhood catastrophic diseases, global impact, and a focus on people and place. In each of these areas, were recruiting new individuals, investing in new technology, and expanding collaborations across campus, across the United States, and globally.

Ill start with fundamental science. In our last strategic plan, we invested heavily in increasing basic science programs on campus by expanding faculty numbers, technology and institutional data infrastructurein the belief that expanding fundamental science leads to new knowledge that helps advance cures. This is investigator-initiated science, often not related to diseases, but rather to the fundamental questions of biology.

In this new plan, were again investing heavily in expanding fundamental science at St. Jude. Weve committed more than $1 billion to fundamental science. This includes increasing laboratory-based faculty by more than 33% during the next six years, and more than $250 million dedicated to investments in technology.

Our goal is to make sure every dollar is spent wisely and effectively in pursuit of our missionto advance cures and means of prevention for pediatric catastrophic diseases through research and treatment.

The $250 million will fund multiple shared resources, department-based technology centers and new centers of excellence. Some of the faculty are being recruited to the centers of excellence, including those in data-driven discovery, innate immunity and inflammation, leukemia and advanced microscopy. These individuals will also have homes in academic departments.

On the technology front, were investing in shared resources. Well bring online some new ones, as well as some (Center for Modeling Pediatric Diseases and the Center for High-Content Screening) created at the end of the last strategic plan. The newest is focused on spatial transcriptomics. It will allow scientists across campus to look at the expression of genes in tissue context and at the single-cell level.

A new effort in structural biology is to create a $20 million Cryo-Electron Tomography Center. This is the next level of cryo-electron microscopy, which allows the identification of the structure of molecules or molecular machines within the context of cells. Its a developing technology that will feed other investments weve made in structural biology, such as the installation of one of the largest magnets in the world in our NMR facility, our Cryo-Electron Microscopy Center and single-cell analysis capabilities. The plan brings those tools to bear on defining normal biology and disease states.

Another effort is a Center of Excellence in Advanced Microscopy. Over the last six years, weve become one of the leading centers in the application of advanced microscopy to fundamental biology. This has been led by investigators in our Developmental Neurobiology, Cell and Molecular Biology, and Immunology departments.

Were positioned to build the next generation of microscopes to explore biology in ways never dreamed. With new faculty recruitments and collaborations with commercial companies and other institutions, we seek to develop the next generation of microscopes, and apply that to normal biology and to pediatric catastrophic diseases.

Another area were investing in heavily is data science. Over the last six years, and even before that, we expanded data sciences across campus. This initially started with the Pediatric Cancer Genome Project in 2010. Since then, we recruited many data scientists, and coalesced them into our Computational Biology, Biostatistics, and Epidemiology and Cancer Control departments, and into shared resources that provide bioinformatics support.

But over the last several years, weve seen the explosion of data, from structural biology to microscopy.

As we look to the future and the capabilities weve amassed, were poised to significantly increase our investment in data science and become a leading institution in the application of data science to biologic discovery. This is a $40 million investment with 30 full-time employees.

We have a task force led by faculty members to develop the roadmap for how were going to move forward. As data is accumulated and we look across those disparate data types, we can gain knowledge through true data scienceexploring that data and advancing our understanding of biology.

The last area in fundamental research is our graduate school. During the last strategic plan, we developed the St. Jude Graduate School of Biomedical Sciences, which offers a PhD and two masters programs.

Were going to expand that over the coming six years by increasing the number of students in the Biomedical Sciences PhD, the Master of Science in Global Child Health and the Master of Science in Clinical Investigations programs. We will also create a new masters program in data science. That will bring a new population of students to campus, which will further enhance our scientific enterprise.

Pediatric cancer is our next area of focus. This has always been our institutions major focus. This area encompasses $3.7 billion of the operating dollars we will spend over the next six years. Although weve invested heavily in this effort in the past, were going to expand it significantly.

Were going to focus on pediatric cancers where the least progress has been madecancers that are incurable and relapsed diseaseand gain insights into how we can change the outlook for those cancers.

The first area of investment is new faculty10 laboratory-based individuals who will expand our research efforts in understanding the biology of cancer. Some of those faculty will go into the Center of Excellence in Leukemia, but others will focus on solid tumors, brain tumors, or on biologic aspects that cut across cancer types.

Our second area for expansion will focus on assessing new therapeutic approaches for the highest-risk cancers. We need to access and evaluate more new therapies in a rigorous manner to identify those which should be moved forward into frontline clinical trials. Pediatric cancer encompasses many different types of cancer.

To run clinical trials, you need a sufficient number of patients to be able to answer questions in a reasonable time frame. We need a way to identify the best new agents to move into clinical trials.

Our investment in preclinical testing will help us set up that infrastructure. Much of it was established in the last strategic plan, but it must be expanded so that we have the best pediatric cancer models and can assess single and combination therapies to see which are worth moving forward into clinical trials.

On the clinical trial front, we want to expand our infrastructure to run those clinical trialsnot only on our campus, but in collaborations across the United States and around the globe. To make progress in some of these high-risk pediatric cancers, we need many patients. For many of the high-risk cancers, there are not a sufficient number of patients in the United States to conduct the trials. We, therefore, need to set up global collaborative networks that can address these high-risk cancers.

So, were investing in our ability to access drugs through commercial sources, to rigorously assess these in preclinical models and to establish the global infrastructure to run these clinical trials with an associated translational science infrastructure second to none.

Our third emphasis under the cancer focus is cancer immunotherapy. We began our work in cancer immunotherapy decades ago. We developed the chimeric antigen receptor, or CAR, against CD-19. That is the basis for the FDA-approved therapy that is being used right now on a variety of different fronts. Over the last several years, weve also invested heavily in expanding our cancer immunotherapy efforts, primarily focused on CAR-modified T cells.

As part of this new strategic plan, we are creating a new program, the Translational Immunology and Immunotherapy Initiative. It will facilitate cross-departmental efforts focused on cancer immunotherapy and will explore the fundamental biology of chimeric antigen receptor approaches to cancer immunotherapy.

What makes an ideal antigen that can be attacked by a chimeric antigen receptor? How does one manipulate CAR T cells so that they undergo exhaustion and stop killing the tumor? How do we change that? And what are the features of the microenvironment that decrease the killing potency of CAR T cells? These will require significant investments, including additional faculty.

Another emphasis will be looking at long-term toxicities of the therapies we use to treat children with cancer. As we cure more and more pediatric cancers, we must continually look at the toxicities from therapy and figure out how to reduce those without sacrificing the ability to be cured. Part of that is precision medicine, and so we are continuing to invest in our genomic and pharmacogenomic efforts and our proton therapy center.

Part of reducing toxicities comes from learning from long-term survivors. So, we will continue to invest in St. Jude LIFE, our long-term, follow-up study. We will expand that to some of the newer pediatric cancer therapies, including immunotherapy and targeted agents. We will assess long-term complications from these therapeutic approaches and try to define which patients will be susceptible to these toxicities.

MO: I have to mention the obvious: $11.5 billion is quite the budget. Your new strategic plan is work that, one could argue, might be on par or exceeds the coordination and budget required to realize multiple projects, say, at the World Health Organization or even at some U.S. federal agencies. What did it take for you and your team at St. Jude to get to this point?

JD: There are an incredible number of donors across the United States who support St. Jude. Our goal is to make sure every dollar is spent wisely and effectively in pursuit of our missionto advance cures and means of prevention for pediatric catastrophic diseases through research and treatment. This carries a great responsibility for us to seek the maximum possible impact to improve outcomes for childhood cancer.

We have the ideal team at St. Jude to execute this. Our leadership meets multiple times each week. Two years ago, we began strategically looking at the most pressing issues in the field of pediatric cancer. We discussed which areas represented the greatest opportunities for St. Jude to contribute. We talked to many experts inside and outside of the institutionaround the globeand made hard decisions as we went forward.

Strategic planning is deeply engrained at St. Jude as a rigorous process that is part of our scientific culture. We knew it was going to take two years to develop this plan. We dont hire consultants; we do it all ourselves. Faculty across the institution participated in the development of priorities and goals for this strategic plan via structured meetings.

As we developed the strategic plan over those two years, there were many ideas we critically assessed, and we often said, Its not really best for St. Jude to pursue that. In the end, we aligned on goals that collectively bring the prospect of remarkable benefits to the field of childhood cancer, and to children with cancer everywhere.

Every child who comes on this campus is part of our mission. We provide them with the best care possible. We do that in the context of research studies, so that were learning from every single patient. That means were not only helping children today; were also advancing cures for children tomorrow.

Weve rolled out the new strategic plan across campus during the last month, and the excitement is palpable. Our commitment continues long after the strategic plans launch.

We have routine strategic planning retreats, where we assess the goals for the year, evaluate progress against the prior years goals, perform talent assessments and proactively seek out emerging opportunities. Every employee on campus will develop yearly goals that cascade down from the goals of this plan.

As we develop this roadmap, we know there are going to be new ideas. Charlie can tell you about a process incorporated into the strategic plan that allows us to not only move forward on this roadmap, but also add initiatives as new ideas emerge.

Charles Roberts: Its a process we began with the last strategic plan, called our blue-sky process. As we launch a strategic plan, weve identified the most exciting opportunities and challenges at that point in time.

However, we fully realize that we dont know whats coming next. New discoveries will be made, and new opportunities will emerge. Via the blue-sky process, weve set aside substantial funds every year to invest in the pursuit of emerging opportunities suggested by faculty and staff.

Ideas that have emerged from the blue-sky process have been phenomenal. Our engagement with World Health Organization (WHO)a collaboration to raise childhood cancer survival rates internationallyis one example.

The Center for Modeling Pediatric Diseases is another example. This center makes iPS cells that come from patients so that we can investigate mechanisms that underlie cancer predisposition.

In another blue-sky project, were looking at DNA methylation to characterize pediatric solid tumors with the goal of identifying new therapeutic opportunities. Some of our immunotherapy initiatives also came out of the blue-sky process. Were looking forward to growing our blue-sky endeavors as we go forward.

Were coming out of a six-year strategic plan in which we increased our number of cancer patients by 20%, with 30% new faculty, 23% more staff, many large-scale construction projects. And were now going into a new strategic plan that is 60% larger than our prior plan.

The other central part of our strategic planning process focuses on the importance of collaboration. We have systematically incorporated a focus upon collaboration into our entire strategic planning and execution process. Our strategic planning efforts began by bringing together the intellectual resources of faculty and staff at St. Jude. This yielded projects that have interactions between many investigators on campus.

We recognize, however, that were still a relatively small institution, and theres a lot of expertise outside. We asked: How can we engage top scientists to tackle problems related to cancer and other catastrophic illnesses of childhood?

In pursuit of this, during our last strategic plan, we created the St. Jude Research Collaboratives, in which we fund investigators from multiple institutions who collaborate with investigators at St. Jude.

Initially, we were planning to fund two or three Collaboratives. However, they were remarkably successful, and top scientists eagerly joined.

Consequently, weve grown the program to five St. Jude Research Collaboratives already. These teams are each funded at an average of $8 million over 5 years, so each investigator is getting R01-level funding, or a little bit better. This has been a phenomenal success.

In the new strategic plan, were going to grow the program to a steady state of 11 funded collaboratives, representing close to a $90 million investment. So far, three of the Collaboratives are directly focused on childhood cancer. A fourth is a basic science-focused project relevant to childhood cancer. Were excited about the growth of this collaboration-focused program.

Lastly, Id like to address global collaboration. If you look across the globe, in low- and middle-income countries, the cure rates for childhood cancer are less than 20%.

This is a problem we know we can solve. Weve proven in the United States we can drive the cure rate to 80%. How can we help the rest of the world?

Because of the resources brought to us by our donors, we are able to think about these things, and so were now collaborating around the globe to drive cure rates forward for childhood cancer worldwide.

JD: As an example of new ideas and how rapidly we can act on them, Id like to tell you about a new blue-sky proposal that came up at the end of the last strategic plan. This idea was precipitated at a faculty retreat. One of our senior investigators was presenting, and during a coffee break, someone said, Well, what if you did this? That emerged into a blue-sky proposal, Seeing the Invisible in Protein Kinases. This was work from Dr. Babis Kalodimos, our Structural Biology department chair. He had a Science paper that came out several months ago, where he used the high-field NMR spectroscopy to look at the structure of the ABL kinase. He was able to identify transient conformational states that help to explain how resistant mutants work.

This gave us new insights into transient states that exist in molecules that can only be seen under high-field NMR, not with other structural biology approaches.

Based on that, we started thinking, Well, what if you did this on all kinases? What if you just did it against tyrosine kinases, serine kinases, receptor tyrosine kinases? What new rules would emerge from this? What would it tell us about families of kinases? What would it tell us about mechanisms of inhibition to kinase inhibitors? What might it tell us about new approaches to developing drugs against protein tyrosine kinases?

And since kinases are a major focus for targeted therapy, there was great excitement about pursuing these studies. Dr. Kalodimos developed the proposal and brought it forward; however, it was clear that this effort would be beyond the scope of our blue-sky process.

Blue-sky initiatives are usually somewhere in the $12 million range, and this was north of $30 million. Yet, in the end after thorough internal and external reviews, the project will move forward as part of the new strategic plan..

This is an approach that will give us fundamental knowledge and can have a profound impact on our understanding of a major class of targets for next-generation therapy.

MO: If I recall accurately, St. Jude has a network of partnerships with a few dozen countries worldwide. Does this plan call for an expansion of efforts within each of those countries? And how many of them?

JD: When I took over in 2014, we had what we called the International Outreach Program, which was 24 programs in 17 countries. During the programs 25-year history, we had made great progress. We were making significant impact and changing the outlook for children with cancer in those 17 countries. But we were affecting only about 3% of children with cancer across the globe, and the International Outreach Program was not scalable.

So, at the beginning of the last strategic plan, we recruited Dr. Carlos Rodriguez-Galindo. He developed a vision that after assessing, we decided to move forward on. This new effort encompasses the Department of Pediatric Global Medicine, St. Jude Global and the St. Jude Global Alliance.

These are all integrated. We developed a model that we think is scalable around the world, and we think this model ultimately can affect children with cancer everywhere.

The idea is that first we must train a workforce to treat children with cancer around the globe. We cant train the workforce ourselves, but we can train the trainers, who will then train the workforce.

More:
St. Jude's $11.5B, six-year plan aims to improve global outcomes for children with cancer and catastrophic diseases - The Cancer Letter

IPS Cell Therapy Comments Off on St. Jude’s $11.5B, six-year plan aims to improve global outcomes for children with cancer and catastrophic diseases – The Cancer Letter | May 15th, 2021

Synthego, the genome engineering company, today announced the launch of Eclipse, a new high-throughput cell engineering platform designed to accelerate drug discovery and validation by providing highly predictable CRISPR-engineered cells at scale through the integration of engineering, bioinformatics, and proprietary science. The launch of this unique CRISPR-based platform is driving the companys growing impact in biopharma R&D, reinforcing Synthegos position as the genome engineering leader.

CRISPR-engineered cells have a wide range of applications in research and development across disease areas, including in neuroscience and oncology. Synthego created the Eclipse Platform to enhance disease modeling, drug target identification and validation, and accelerate cell therapy manufacturing.

"By industrializing cell engineering, Synthegos Eclipse Platform will enable economies of scale, turning a historically complex process into one that is flexible, reliable, and affordable, said Bill Skarnes, Ph.D., professor and director of Cellular Engineering at The Jackson Laboratory and Synthego advisory board member. Offering CRISPR edits at scale, similar to what Synthego did with sgRNA reagents, puts researchers on the cusp of being able to study thousands of genes, and examine hundreds of variants of those genes. This will allow scientists to more faithfully model the complexity of a human disease, which could lead to the development of therapeutic drugs or next-generation gene therapies for many serious diseases.

To ensure the success of any type of edit, Eclipse uses machine learning to apply experience from several hundred thousand genome edits across hundreds of cell types. With this machine learning, combined with automation, the new platform can reduce costs and increase the scalability of engineered cell production. The Eclipse Platform is modular in design, allowing for fast deployment of upgrades or add-ons. It is engineered to use a cell-type agnostic process and immediately benefit researchers working with induced pluripotent stem (iPS) cells and immortalized cell lines.

We are living in a new era of life sciences innovation one that has added to DNA sequencing and being able to read out of biology, now being able to write into and engineer biology. We created our Eclipse Platform at the convergence of science and technology to make genome editing more precise, scalable, and accessible, said Paul Dabrowski, CEO and co-founder of Synthego. We are excited to expand our impact on advancing the life sciences innovation with the launch of this unique CRISPR-based platform.

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Synthego Launches Eclipse Platform to Accelerate Research and Development of Next-generation Medicines - The Scientist

IPS Cell Therapy Comments Off on Synthego Launches Eclipse Platform to Accelerate Research and Development of Next-generation Medicines – The Scientist | April 19th, 2021

Google is discontinuing the Google Play Movies and TV app for Samsung, LG and Vizio smart TVs, as well as Roku devices. Come June 15th, 2021, you wont be able to access the software on those platforms anymore. Instead, youll need to go through YouTube to watch any content youve bought in the past. Any Google Play credits associated with your account will still be there, allowing you to buy new movies and TV shows. However, your Watchlist wont transfer over, and support for family sharing is more limited.

Google shared the news last month, but it went mostly unnoticed until after websites like Liliputing and 9to5Google published stories on the shutdown earlier today following an email the company sent to users. To be clear, Play Movies and TV itself isnt joining the Google graveyard on June 15th. Google plans to eventually merge the app with its new Google TV software, but that's an ongoing process with the former still available to download on Android and iOS.

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The Google Play video app will leave Roku, Vizio, LG and Samsung's TV platforms - Yahoo Canada Finance

IPS Cell Therapy Comments Off on The Google Play video app will leave Roku, Vizio, LG and Samsung’s TV platforms – Yahoo Canada Finance | April 19th, 2021

By Jonny Lupsha, Current Events WriterAn alternative to using human embryonic stem cells is to use pluripotent stem cells, which refers to the ability of a stem cell, such as skin cells from an adult, to give rise to other differentiated cell types. Photo By Yurchanka Siarhei / Shutterstock

Patients who have received treatment from their own stem cells to repair their spinal cords are at the center of controversy after the stem cell therapy was fast-tracked in Japan in 2018. Despite 13 patients showing considerable recovery in response to the treatment, the means to this end have suggested improper shortcuts taken in the last several years.

It isnt the first time that stem cell research has been in the spotlight for ethical reasons. One controversial method of obtaining stem cells is to take them from human embryos, which has been argued about for decades. However, alternatives to embryo use are coming to pass.

In his video series Biochemistry and Molecular Biology: How Life Works, Dr. Kevin Ahern, Professor of Biochemistry and Biophysics at Oregon State University, said much about stem cells and the science that surrounds them.

There are two things that are special about stem cells, Dr. Ahern said. One is that they are capable of dividing indefinitelythat is, as long as the organism is alive. The other is that they are undifferentiatedtheyre like a child who hasnt yet chosen whether to be an astronaut, ballerina, surgeon, or an artist.

Dr. Ahern said that when stem cells divide, they can either differentiate and become a specialized cell or they can go back into the stock of stem cells. In an embryo, at the earliest stages of development, the fertilized egg divides to produce a certain number of unspecialized cells called embryonic stem cells. They become specialized by receiving certain signals, so scientists can learn what these signals are and send them to unspecialized cells to make them develop as they wish. This could mean making them become cells to repair nerve damage, heart muscles, and more.

However, some see this as tampering with nature and/or stealing cells from the embryo. Regardless of our opinions one way or the other, these ethical concerns have been raised, prompting scientists to find alternatives.

How else can stem cells be obtained, if not from embryos?

One solution is the production of what are called induced pluripotent stem cells, or iPS cells, Dr. Ahern said. Pluripotent refers to the ability of a stem cell to give rise to other differentiated cell types. To do this and yet avoid working with cells from a human embryo, scientists begin with differentiated somatic cells [like] cells from the skin of an adult, for example.

Once theyve isolated the differentiated somatic cells, scientists reverse engineer them into a state in which they can become any number of differentiated cells or tissues. Dr. Ahern said that iPS cells have been used to create beating heart cells, motor neurons, light-sensing photoreceptor cells, insulin-producing pancreatic cells, and more.

In 2017, Japanese researchers reported that monkeys with Parkinsons showed great improvement after treatment with dopamine-producing neurons derived from iPS cells, Dr. Ahern said. In 2018, clinical trials with humans were begun using iPS cells to treat Parkinsons, heart disease, and macular degeneration.

For now, stem cell therapy remains no stranger to controversyor results. The debate raging around them will likely continue in one way or another for some time.

Edited by Angela Shoemaker, The Great Courses Daily

Originally posted here:
New Controversy for Stem Cell Therapy That Repairs Spinal Cords - The Great Courses Daily News

IPS Cell Therapy Comments Off on New Controversy for Stem Cell Therapy That Repairs Spinal Cords – The Great Courses Daily News | March 8th, 2021

Pierluigi Porcu, MD, director, Medical Oncology and Hematopoietic Stem Cell Transplantation and coleader, Immune Cell Regulation and Targeting Program, Sidney Kimmel Cancer Center, at Jefferson Health in Philadelphia, PA, explained how the combination of brentuximab vedotin plus chemotherapy works in in frontline Hodgkin lymphoma.

Targeted OncologyTM: Following a diagnosis of classical Hodgkin lymphoma, nodular sclerosis type, what additional molecular testing should be ordered?

PORCU: PD-1 and PD-L1; I think most hematopathology labs nowadays run PD-1 and PD-L1 on Hodgkin [lymphoma] cases. Certainly, most hematopathology labs run CD30, although they may not run it on non-Hodgkin lymphoma cases on a routine basis.

Barr virus [EBV]. Its an in situ hybridization test thats fairly routine and not very expensive. It identifies cases of Hodgkin lymphoma that are EBV positive. Its important because there are some pretty good data that [show] EBV identifies a subgroup of Hodgkin lymphoma that has an inferior prognosis in terms of progression-free survival [PFS]. [Its also important because] there are now treatments for relapsed patients who have EBV-positive lymphoma including Hodgkin.

In some cases, the diagnosis is complex. You may have a gray-zone lymphoma or primary mediastinal B-cell lymphoma, [so its important] to have additional markers more in the space of diffuse large B-cell lymphoma to make sure.

In very difficult cases, the other testing would be immunoglobulin heavy chain gene rearrangement. This is routinely negative in Hodgkin lymphoma because the immunoglobulin in genes is aberrantly rearranged and mutated.

Why is PD-1 testing needed for diagnosis?

It doesnt affect diagnosis. Its part of the characterization of the Hodgkin lymphoma as a whole. I use it as a routine initial assessment because you never know when patients come back to have a second biopsy how easy it [will be] to get the tissue the second time around.

Can you discuss the International Prognostic Score [IPS]?

The IPS, [also called the Hasenclever index], was published in 1998 and is specifically for advanced-stage serum albumin level of less than 4; a hemoglobin level of less than 10.5; male sex; age equal to or older than 45; stage IV disease; and total WBC count of more than 15,000 or a lymphocyte count of less than 600, less than 8% of the WBC count, or both.1 The patient here has a number of these items. She has a hemoglobin of 9.5, stage IV disease, a WBC count higher than 15,000, and a lymphocyte count less than 600. Her IPS is 4. Based on the data from Hasenclever, her 5-year overall survival [OS] rate is 61%. Interestingly enough, [British Columbia Cancer] looked at their data in terms of the Hasenclever classes and found that for the patients with the highest scores, over time, some of these 5-year survivals were better, but not for the lower ones.

In addition, even though the lymphocyte count is part of the canonical standard, lymphopenia is a common phenomenon in most lymphomas. I follow it closely in T-cell lymphomas, where its common for people to have lymphocyte counts less than 500 and certainly less than 250 in AIDS territory, even though they dont have a history of opportunistic infection. I think the lymphocyte count is clearly an important biological flag marker, although we dont quite know what the biology of that is.

What are your thoughts on the options provided in the poll and the results?

Essentially here, were talking about SWOG S0816 [NCT00822120] or the RATHL [NCT00678327] clinical trial [regimens]. Straight-up escalated BEACOPP [bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, prednisone] German style, brentuximab vedotin [BV; Adcetris] with AVD [doxorubicin, vinblastine, dacarbazine] according to the ECHELON-1 [NCT01712490] trial, or other.

There were 4 votes for PET-adapted therapy with ABVD [doxorubicin, bleomycin, vinblastine, dacarbazine]. We have 7 who voted for BV plus AVD. No votes for escalated BEACOPP, which, even though its perfectly appropriate, Im happy to see [no votes for] because Im not a fan of escalated BEACOPP, and no [votes for] other. The majority would vote for the ECHELON-1 approach for this particular patient.

What frontline systemic therapy are you most likely to recommend for this patient?

Theres no role for radiation therapy. I think the jury is still out regarding PET-adapted therapy versus nonPET-adapted therapy. When I approach patients with advanced-stage disease, I look at a couple of things. One is, which risk category do they really belong to? The other is that PET-adapted therapy is dependent on the PET [scan]. Good-quality reading of PET scans is far from common; they dont give you Deauville [score]. Its unclear how they reach their conclusion because they dont compare the mediastinal and liver to the hypermetabolic lymph nodes. Its not that easy to get a good highquality PET interpretation, and if youre making these big decisions about the escalationor rather, in my case, deescalation according to the RATHL trialthen not having a goodquality PET is a big problem.

One of the big things about frontline therapy is that now we try to avoid exposure to bleomycin. There are 2 ways of doing that: Pick BV and AVD or treat the patient according to RATHL. Thats if the PET is negative; then you can deescalate and remove the bleomycin from the last 4 cycles of ABVD.2

Which factors do you think are most important?

It looks like everyone is on the same page as far as lung function and lung issues [if] someone is a heavy smoker or has a previous history of lung disease. Its not common in young people but certainly more common in middleaged or older people. Then, obviously, the selection of the therapy is important. The BV plus AVD had less lung toxicity compared to AVD, but its not that they had no lung toxicity. You still have to be worried somewhat and monitor people carefully on this therapy, even if it doesnt have bleomycin. Then for the PET-adapted ABVD, like RATHL, the first 2 cycles still contain bleomycin. Certainly, that is fundamental.

Here we have lung disease, prognostic score, performance. Age is really, in my practice, an important part of the decision-making because its not very common. Patients who are older than 60 or 65 generally represent no more than 20% of the cases of Hodgkin lymphoma. But when you have those patientsIm sure you all have seen them in your practicetheir prognosis is particularly bad, especially for those who are older than 70. Selecting the proper therapy for those patients is difficult and, of course, there are trials currently going on. Some of them have been published. For example, BV and bendamustine is one option. There are also trials with single-agent BV ongoing for patients who are frail on the front line. Besides, of course, all the combinations with checkpoint inhibitors...Theres quite a bit going on. For me, age is a very important component of decision-making.

Can you discuss the findings of the ECHELON-1 trial?

Following the initial phase 1 trial, data from ECHELON-1 showed that you cant give BV with ABVD because of a high rate of pulmonary toxicity. Finding the right dose of BV [is important] because it has to be given every 2 weeks. There are several dose-escalation records in phase 1, but 1.2 mg/kg was found to be the right tolerable dose for this schedule.

This was a large study of 1334 patients who were randomized 1:1 to receive 6 cycles of ABVD or 6 cycles of BV plus AVD. There was an interim PET scan, mostly to assess the response but not to be acted on, except for Deauville 5. [Those participants] would be given the opportunity to receive alternative therapy, and this was not part of the modified PFS scoring. Then there was an end of therapy CT-PET scan. Standard follow-up inclusion criteria [included] classical Hodgkin lymphoma that was stage III and IV, up to an ECOG performance status of 2, more than 18 years old, measurable disease, and adequate organ function. The primary end point was modified PFS, and a key secondary end point was OS.3

The initial paper was published in the New England Journal of Medicine in early 2018 with 2-year PFS data.3 But follow-up data [presented during the 2020 American Society of Hematology Annual Meeting and Exposition] show a median follow-up of 55.6 months with PFS of 82% [95% CI, 78.7%-84.8%] for BV plus AVD versus 75.2% [95% CI, 71.5%-78.4%] for ABVD. There is an advantage in terms of PFS.4 OS was no different between the 2 cohorts.

Not all the subgroups had a clear advantage, but younger patients, less than 45, and patients with the highest IPS did. There was an odd distinction: The North American cases appeared to have a stronger benefit compared with the European cases. I dont think anyone has a good explanation for that at this point. In addition, male sex and good performance status seem to be falling on the side of the fence that has a greater gain from BV plus AVD.5

In terms of adverse events [AEs], peripheral neuropathy was more common in the BV plus AVD group compared with the ABVD group [67% vs 43%, respectively]. There were also some gastrointestinal AEs, [including diarrhea (27% vs 18%, respectively) and abdominal pain (21% vs 10%)]. Overall, the 2 cohorts were fairly comparable in terms of overall AEs, except for...a greater number of hospitalizations and infections in the BV plus AVD cohort, which then led to the amendment toward the end of enrollment.3

Key toxicities are pulmonary toxicity and infections and neutropenia. Pulmonary toxicity was seen in both the BV plus AVD and ABVD cohorts, but ABVD had a significantly greater rate of pulmonary toxicity. In terms of on-study death, there were 9 deaths on the BV plus AVD cohort, and of those, 7 were from neutropenia or neutropenic infection. On the other hand, there were 13 deaths on the ABVD cohort, and the majority of them were because of pulmonary toxicity.3

Was the peripheral neuropathy reversible?

Eighty-four percent in the BV plus AVD cohort and 86% in the AVBD cohort reported complete resolution of peripheral neuropathy at almost 5 years. The median to improvement was 30 weeks for BV plus AVD and 16 weeks for AVBD, and then there was a subset that had ongoing neuropathy, mostly grades 1 and grade 2.4

In terms of survivorship, what guidance do you offer patients?

We still dont know much about safety from the standpoint of fertility. In this study, there were a good number of pregnancies and deliveries with healthy babies in women who participated.

Historically, there is a large body of data showing that the impact of ABVD, particularly 6 cycles of ABVD, is trivial to minimal in terms of fertility. Therefore, for patients treated with ABVD, I only [recommend] fertility consultation if the patient or the spouse has a significant degree of anxiousness about it. The other thing I always tell patients about fertilityand this is true for any diseaseis that its impossible to figure out what your fertility is if you never had kids. If someone had children already, then you know that their baseline fertility is standard or average. Its there. If they never did, then its impossible to say what it will be following treatment with anything.

We also dont know what the impact is going to be on second-line efficacy. BV is not going to be a weapon in your toolbox when people progress after BV plus AVD. I think that these are the big questions that we have that require long-term followup. Im selective with the patients that I treat with BV plus AVD. Certainly, for the younger patients, less than age 45, and patients who have advanced stage or high IPS scores, I tend to use this frontline approach. For the others, Im less enthusiastic about using it. I think the financial cost is worth it in those subgroups, including the risk to some degree, but it may not be in the others.

Is progressive multifocal leukoencephalopathy [PML] a concern?

Yes, there is some concern. Im very familiar with the PML cases that were diagnosed in patients who were treated with BV as a single agent with T-cell lymphoma. This is something that I mention to patients as a possible long-term, very severe risk, just like you have the same [risk] when you give Rituxan [rituximab]. I think there should be a concern, but its a minimal concern for this population based on the data that we have.

REFERENCES:

1. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkins disease. International Prognostic Factors Project on advanced Hodgkins disease. N Engl J Med. 1998;339(21):1506-1514. doi:10.1056/NEJM199811193392104

2. NCCN. Clinical Practice Guidelines in Oncology. Hodgkin lymphoma, version 2.2021. Accessed February 1, 2021. https://bit.ly/3oDAEZ4

3. Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkins lymphoma. N Engl J Med. 2018;378(4):331-344. doi:10.1056/NEJMoa1708984

4. Straus DJ, Dugosz-Danecka M, Connors J, et al. Brentuximab vedotin with chemotherapy for patients with previously untreated, stage III/IV classical Hodgkin lymphoma: 5-year update of the ECHELON-1 study. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Accessed February 4, 2021. https://bit.ly/3pKKnx7

5. Straus DJ, Dugosz-Danecka M, Alekseev S, et al. Brentuximab vedotin with chemotherapy for stage III/IV classical Hodgkin lymphoma: 3-year update of the ECHELON-1 study. Blood. 2020;135(10):735-742. doi:10.1182/ blood.2019003127

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Brentuximab Vedotin Plus Chemotherapy Works as a Primary Option for Hodgkin Lymphoma - Targeted Oncology

IPS Cell Therapy Comments Off on Brentuximab Vedotin Plus Chemotherapy Works as a Primary Option for Hodgkin Lymphoma – Targeted Oncology | March 8th, 2021

Abstract

Terminally differentiated murine osteocytes and adipocytes can be reprogrammed using platelet-derived growth factorAB and 5-azacytidine into multipotent stem cells with stromal cell characteristics. We have now optimized culture conditions to reprogram human adipocytes into induced multipotent stem (iMS) cells and characterized their molecular and functional properties. Although the basal transcriptomes of adipocyte-derived iMS cells and adipose tissuederived mesenchymal stem cells were similar, there were changes in histone modifications and CpG methylation at cis-regulatory regions consistent with an epigenetic landscape that was primed for tissue development and differentiation. In a non-specific tissue injury xenograft model, iMS cells contributed directly to muscle, bone, cartilage, and blood vessels, with no evidence of teratogenic potential. In a cardiotoxin muscle injury model, iMS cells contributed specifically to satellite cells and myofibers without ectopic tissue formation. Together, human adipocytederived iMS cells regenerate tissues in a context-dependent manner without ectopic or neoplastic growth.

The goal of regenerative medicine is to restore function by reconstituting dysfunctional tissues. Most tissues have a reservoir of tissue-resident stem cells with restricted cell fates suited to the regeneration of the tissue in which they reside (14). The innate regenerative capacity of a tissue is broadly related to the basal rate of tissue turnover, the health of resident stem cells, and the hostility of the local environment. Bone marrow transplants and tissue grafts are frequently used in clinical practice but for most tissues, harvesting and expanding stem and progenitor cells are currently not a viable option (5, 6). Given these constraints, research efforts have been focused on converting terminally differentiated cells into pluripotent or lineage-restricted stem cells (7, 8). However, tissues are often a complex mix of diverse cell types that are derived from distinct stem cells. Therefore, multipotent stem cells may have advantages over tissue-specific stem cells. To be of use in regenerative medicine, these cells would need to respond appropriately to regional cues and participate in context-dependent tissue regeneration without forming ectopic tissues or teratomas. Mesenchymal stem cells (MSCs) were thought to have some of these characteristics (911), but despite numerous ongoing clinical trials, evidence for their direct contribution to new tissue formation in humans is sparse, either due to the lack of sufficient means to trace cell fate in hosts in vivo or failure of these cells to regenerate tissues (12, 13).

We previously reported a method by which primary terminally differentiated somatic cells could be converted into multipotent stem cells, which we termed as induced multipotent stem (iMS) cells (14). These cells were generated by transiently culturing primary mouse osteocytes in medium supplemented with azacitidine (AZA; 2 days) and platelet-derived growth factorAB (PDGF-AB; 8 days). Although the precise mechanisms by which these agents promoted cell conversion was unclear, the net effect was reduced DNA methylation at the OCT4 promoter and reexpression of pluripotency factors (OCT4, KLF4, SOX2, c-MYC, SSEA-1, and NANOG) in 2 to 4% of treated osteocytes. iMS cells resembled MSCs with comparable morphology, cell surface phenotype, colony-forming unit fibroblast (CFU-F), long-term growth, clonogenicity, and multilineage in vitro differentiation potential. iMS cells also contributed directly to in vivo tissue regeneration and did so in a context-dependent manner without forming teratomas. In proof-of-principle experiments, we also showed that primary mouse and human adipocytes could be converted into long-term repopulating CFU-Fs by this method using a suitably modified protocol (14).

AZA, one of the agents used in this protocol, is a cytidine nucleoside analog and a DNA hypomethylating agent that is routinely used in clinical practice for patients with higher-risk myelodysplastic syndrome (MDS) and for elderly patients with acute myeloid leukemia (AML) who are intolerant to intensive chemotherapy (15, 16). AZA is incorporated primarily into RNA, disrupting transcription and protein synthesis. However, 10 to 35% of drug is incorporated into DNA resulting in the entrapment and depletion of DNA methyltransferases and suppression of DNA methylation (17). Although the relationship between DNA hypomethylation and therapeutic efficacy in MDS/AML is unclear, AZA is known to induce an interferon response and apoptosis in proliferating cells (1820). PDGF-AB, the other critical reprogramming agent, is one of five PDGF isoforms (PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD), which bind to one of two PDGF receptors (PDGFR and PDGFR) (21). PDGF isoforms are potent mitogens for mesenchymal cells, and recombinant human (rh)PDGF-BB is used as an osteoinductive agent in the clinic (22). PDGF-AB binds preferentially to PDGFR and induces PDGFR- homodimers or PDGFR- heterodimers. These are activated by autophosphorylation to create docking sites for a variety of downstream signaling molecules (23). Although we have previously demonstrated induction of CFU-Fs from human adipocytes using PDGF-AB/AZA (14), the molecular changes, which underlie conversion, and the multilineage differentiation potential and in vivo regenerative capacity of the converted cells have not been determined.

Here, we report an optimized PDGF-AB/AZA treatment protocol that was used to convert primary human adipocytes, a tissue source that is easily accessible and requires minimal manipulation, from adult donors aged 27 to 66 years into iMS cells with long-term repopulating capacity and multilineage differentiation potential. We also report the molecular landscape of these human iMS cells along with that of MSCs derived from matched adipose tissues and the comparative in vivo regenerative and teratogenic potential of these cells in mouse xenograft models.

Primary mature human adipocytes were harvested from subcutaneous fat (Fig. 1A and table S1) and their purity confirmed by flow cytometry with specific attention to the absence of contaminating adipose-derived MSCs (AdMSCs) (fig. S1, A and B). As previously described (14), plastic adherent adipocytes were cultured in Alpha Minimum Essential Medium (MEM) containing rhPDGF-AB (200 ng/ml) and 20% autologous serum (AS) with and without 10 M AZA for 2 and 23 days, respectively (Fig. 1A). During daily observations, unilocular lipid globules were observed to fragment within adipocytes ~day 10 with progressive extrusion of fat into culture medium, coincident with changes in cell morphology (movie S1). Consistent with these observations, when fixed and stained with Oil Red O, adipocytes that were globular in shape at the start of culture resembled lipid laden stromal cells at day 12 and lipid-free stromal cells at day 25 (Fig. 1B).

(A) Generation and reprogramming of adipocytes. (B) Oil Red Ostained adipocytes (days 0, 12, and 25) during treatment with recombinant human platelet-derived growth factorAB (rhPDGF-AB) and AZA. (C) Flow cytometry plots of LipidTOX and PDGFR in adipocytes cultured as in (A). (D) CFU-F counts from treated and untreated adipocytes during conversion. (E) CFU-F counts from adipocytes treated (Rx) with indicated combinations of rhPDGF-AB, AZA, fetal calf serum (FCS), autologous serum (AS), or serum-free media (SFM). (F) CFU-F counts from adipocytes reprogrammed in the presence of 0, 1, or 10 M PDGFR/ inhibitor AG1296. (G) CFU-F counts per 400 reprogrammed adipocytes from three donor age groups (n = 3 for each) generated using indicated combinations of rhPDGF-AB and AZA. (H) Long-term growth of reprogrammed adipocytes from three donor age groups (n = 3 for each) generated using indicated combinations of rhPDGF-AB and AZA. (I) Long-term growth of iMS cells cultured in SFM or media supplemented with FCS, autologous, or allogeneic serum. Error bars indicate SD, n = 3; *P < 0.05, **P < 0.01, and ***P < 0.0001 calculated using either a Students t test (E and F) or a linear mixed model (H). Photo credit: Avani Yeola, UNSW Sydney.

To evaluate these changes in individual cells, we performed flow cytometry at multiple time points during treatment and probed for adipocyte (LipidTOX) (24) and stromal cell characteristics [PDGFR expression (25); Fig. 1C]. A subpopulation of adipocytes, when cultured in media supplemented with PDGF-AB/AZA and AS (Fig. 1C, top; treated), showed reduced LipidTOX staining intensity at day 10, with progressive reduction and complete absence in all cells by day 19. Adipocytes cultured in the absence of PDGF-AB/AZA retained LipidTOX staining, albeit with reduced intensity (Fig. 1C, bottom; untreated). Adipocytes expressed PDGFR [fig. S1C, (i) and (ii)] but not PDGFR (Fig. 1C) at day 0 but both the frequency and intensity of PDGFR staining increased from day 21. To record these changes in real time, we also continuously live-imaged treated adipocytes from days 15 to 25 and recorded the extrusion of fat globules, change in cell morphology from globular to stromal, and acquisition of cell motility and cell mitosis (movie S1 and fig. S1D). Intracellular fragmentation of fat globules was observed over time in untreated adipocytes (fig. S1E), consistent with variable LipidTOX staining intensity. CFU-F capacity was absent at day 10, present in day 15 cultures, and tripled by day 19 with no substantial increase at days 21, 23, and 25 (Fig. 1D). It is noteworthy that CFU-F potential was acquired before PDGFRA surface expression when adipocytes had started to display stromal cell morphology and had diminished fat content. There was also no CFU-F capacity in adipocytes cultured in MEM with fetal calf serum (FCS) or AS, unless supplemented with both PDGF-AB and AZA. CFU-F capacity was significantly higher with AS than with FCS and absent in serum-free media (SFM) (Fig. 1E and fig. S1F). As previously shown with reprogramming of murine osteocytes, there was dose-dependent inhibition of CFU-F capacity when AG1296, a potent nonselective PDGF receptor tyrosine kinase inhibitor (26), was added to the reprogramming media (Fig. 1F).

To evaluate the impact of patient age and concentrations of PDGF-AB and AZA on the efficiency of human adipocyte conversion, we harvested subcutaneous fat from donors aged 40 (n = 3), 41 to 60 (n = 3), and 61 (n = 3) years and subjected each to three different concentrations of PDGF-AB (100, 200, and 400 ng/ml) and three different concentrations of AZA (5, 10, and 20 M) (Fig. 1G). Although all combinations supported cell conversion in all donors across the three age groups, rhPDGF-AB (400 ng/ml) and 5 M AZA yielded the highest number of CFU-Fs (Fig. 1G). When these cultures were serially passaged in SFM (with no PDGF-AB/AZA supplementation, which was used for cell conversion only), adipocytes converted with reprogramming media containing rhPDGF-AB (400 ng/ml) and 5 M AZA were sustained the longest (Fig. 1H, fig. S2A, and table S2). The growth plateau that was observed even with these cultures [i.e., adipocytes converted with rhPDGF-AB (400 ng/ml) and 5 M AZA when expanded in SFM or FCS] was overcome when cells were expanded in either autologous or allogeneic human serum (Fig. 1I). The genetic stability of human iMS cells (RM0072 and RM0073) was also assessed using single-nucleotide polymorphism arrays and shown to have a normal copy number profile at a resolution of 250 kb (fig. S2B). Together, these data identify an optimized protocol for converting human primary adipocytes from donors across different age groups and show that these can be maintained long term in culture.

Given the stromal characteristics observed in human adipocytes treated with PDGF-AB/AZA (Fig. 1), we performed flow cytometry to evaluate their expression of MSC markers CD73, CD90, CD105, and STRO1 (13) and noted expression levels comparable to AdMSCs extracted from the same subcutaneous fat harvest (Fig. 2A). Primary untreated adipocytes (day 25 in culture) did not express any of these MSC markers (fig. S3A). The global transcriptomes of iMS cells and matched AdMSCs were distinct from untreated control adipocytes but were broadly related to each other [Fig. 2B, (i) and (ii)]. Ingenuity pathway analysis (IPA) using genes that were differentially expressed between AdMSCs versus adipocytes [3307 UP/4351 DOWN in AdMSCs versus adipocytes; false discovery rate (FDR) 0.05] and iMS versus adipocytes (3311 UP/4400 DOWN in iMS versus adipocytes; FDR 0.05) showed changes associated with gene expression, posttranslational modification, and cell survival pathways and organismal survival and systems development [Fig. 2B(iii)]. The number of differentially expressed genes between iMS cells and AdMSCs was limited (2 UP/26 DOWN in iMS versus AdMSCs; FDR 0.05) and too few for confident IPA annotation. All differentially expressed genes and IPA annotations are shown in table S3 (A to E, respectively).

(A) Flow cytometry for stromal markers on AdMSCs (green) and iMS cells (purple) from matched donors. Gray, unstained controls. (B) (i) Principal components analysis (PCA) plot of adipocyte, AdMSC, and iMS transcriptomes. (ii) Hierarchical clustering of differentially expressed genes (DEGs, FDR 0.05). (iii) Ingenuity pathway analysis (IPA) of DEG between AdMSCs/adipocytes (top) or iMS cells/adipocytes (bottom). The most enriched annotated biological functions are shown. (C) (i) Chromatin immunoprecipitation sequencing (ChIP-seq) profiles in AdMSCs and iMS cells from matched donors at a representative locus. Gray bar indicates differential enrichment. (ii) Volcano plots of H3K4me3, H3K27Ac, and H3K27me3 enrichment peaks significantly UP (red) or DOWN (blue) in iMS cells versus AdMSCs. (iii) IPA of corresponding genes. log2FC, log2 fold change. (D) (i) DNA methylation at a representative locus in AdMSCs and iMS cells from matched donors. (ii) Volcano plot of regions with significantly higher (red) or lower (blue) DNA methylation in iMS cells versus AdMSCs. (iii) IPA using genes corresponding to differentially methylated regions (DMRs). (E) OCT4, NANOG, and SOX2 expression in iPS, AdMSCs, and iMS cells. Percentage of cells expressing each protein is indicated. DAPI, 4,6-diamidino-2-phenylindole. (F) AdMSCs and iMS cells differentiated in vitro. Bar graphs quantify staining frequencies, error bars show SD, n = 3. ***P < 0.001 (Students t test). Photo credit: Avani Yeola, UNSW Sydney.

In the absence of significant basal differences in the transcriptomes of AdMSCs and iMS cells, and the use of a hypomethylating agent to induce adipocyte conversion into iMS cells, we examined global enrichment profiles of histone marks associated with transcriptionally active (H3K4me3 and H3K27Ac) and inactive (H3K27me3) chromatin. There were differences in enrichment of specific histone marks in matched AdMSCs versus iMS cells at gene promoters and distal regulatory regions [Fig. 2C(i) and fig. S3, B to D]. H3K4me3, H3K27ac, and H3K27me3 enrichments were significantly higher at 255, 107, and 549 regions and significantly lower at 222, 78, and 98 regions in iMS cells versus AdMSCs [Fig. 2C(ii) and table S4, A to C] and were assigned to 237, 84, and 350 and 191, 58, and 67 genes, respectively. IPA was performed using these gene lists to identify biological functions that may be primed in iMS cells relative to AdMSCs [Fig. 2C(iii) and table S4, D to F]. Among these biological functions, annotations for molecular and cellular function (cellular movement, development, growth, and proliferation) and systems development (general; embryonic and tissue development and specific; cardiovascular, skeletal and muscular, and hematological) featured strongly and overlapped across the different epigenetic marks.

We extended these analyses to also assess global CpG methylation in matched AdMSCs and iMS cells using reduced representation bisulfite sequencing [RRBS; (27)]. Again, there were loci with differentially methylated regions (DMRs) in iMS cells versus AdMSCs [Fig. 2D(i)] with increased methylation at 158 and reduced methylation at 397 regions among all regions assessed [Fig. 2D(ii) and table S4G]. IPA of genes associated with these DMRs showed a notable overlap in annotated biological functions [Fig. 2D(iii) and table S4H] with those associated with differential H3K4me3, H3K27Ac, and H3K27me3 enrichment [Fig. 2C(iii) and table S4, E to G]. Together, these data imply that although basal transcriptomic differences between iMS cells and AdMSCs were limited, there were notable differences in epigenetic profiles at cis-regulatory regions of genes that were associated with cellular growth and systems development.

We next compared iMS cells to adipocytes from which they were derived. Expression of genes associated with adipogenesis was depleted in iMS cells (fig. S4A and table S4I). The promoter regions of these genes in iMS cells had broadly retained an active histone mark (H3K4me3), but, in contrast with adipocytes, many had acquired an inactive mark (H3K27me3) (fig. S4B and table S4J). However, there were examples where iMS cells had lost active histone marks (H3K4me3 and H3K27ac) at gene promoters and potential regulatory regions and gained repressive H3K27me3 [e.g., ADIPOQ; fig. S4C(i)]. In contrast, stromal genes had acquired active histone marks and lost repressive H3K27me3 [e.g. EPH2A; fig. S4C(ii)]. It is noteworthy that promoter regions of genes associated with muscle and pericytes (table S4K) were enriched for active histone marks in iMS cells compared with adipocytes [fig. S4D, (i) and (ii)]. We also compared demethylated CpGs in iMS cells and adipocytes (fig. S4E). There were 7366 sites in 2971 genes that were hypomethylated in iMS cells, of which 236 showed increased expression and were enriched for genes associated with tissue development and cellular growth and proliferation (fig. S4E).

PDGF-AB/AZAtreated murine osteocytes (murine iMS cells), but not bone-derived MSCs, expressed pluripotency associated genes, which were detectable by immunohistochemistry in 1 to 4% of cells (14). To evaluate expression in reprogrammed human cells, PDGF-AB/AZAtreated human adipocytes and matched AdMSCs were stained for OCT4, NANOG, and SOX2 with expression noted in 2, 0.5, and 3.5% of iMS cells respectively, but no expression was detected in AdMSCs (Fig. 2E). In addition to these transcription factors, we also evaluated surface expression of TRA-1-60 and SSEA4. Both proteins were uniformly expressed on iPSCs and absent in AdMSCs [fig. S4F(i)] and adipocytes [fig. S4F(ii)]. Although TRA-1-60 was absent in iMS cells, most (78%) expressed SSEA4 but rarely (<1%) coexpressed OCT4 and NANOG [fig. S4F(i)].

MSCs can be induced to differentiate in vitro into various cell lineages in response to specific cytokines and culture conditions. To evaluate the in vitro plasticity of human iMS cells, we induced their differentiation along with matched AdMSCs and primary adipocytes, into bone, fat, and cartilage, as well as into other mesodermal Matrigel tube-forming assays for endothelial cells (CD31) and pericytes (PDGFR) and muscle (MYH, myosin heavy chain; SMA, smooth muscle actin), endodermal (hepatocyte; HNF4, hepatocyte nuclear factor ), and neuroectodermal (TUJ1; neuron specific class III beta tubulin) lineages (Fig. 2F and fig. S4G). Whereas primary adipocytes remained as such and were resistant to transdifferentiation, iMS cells and AdMSCs showed comparable differentiation potential with the notable exception that only iMS cells generated pericyte-lined endothelial tubes in Matrigel. In keeping with these findings, relative to AdMSCs, iMS cells showed permissive epigenetic marks at pericyte genes [increased H3K4me3 and H3K27Ac; EPHA2 and MCAM; fig. S4H(i); and reduced CpG methylation; NOTCH1, SMAD7, TIMP2, AKT1, and VWF; fig. S4H(ii)]. Together with the notable differences in epigenetic profiles, these functional differences and low-level expression of pluripotency genes in iMS cell subsets suggested that these cells could be more amenable than matched AdMSCs to respond to developmental cues in vivo.

To evaluate spontaneous teratoma formation and in vivo plasticity of iMS cells, we tagged these cells and their matched AdMSCs with a dual lentiviral reporter, LeGO-iG2-Luc2 (28), that expresses both green fluorescent protein (GFP) and luciferase under the control of the cytomegalovirus promoter (Fig. 3A). To test teratoma-initiating capacity, we implanted tagged cells under the right kidney capsules of NOD Scid Gamma (NSG) mice (n = 3 per treatment group) after confirming luciferase/GFP expression in cells in culture (fig. S5, A and B). Weekly bioluminescence imaging (BLI) confirmed retention of cells in situ [Fig. 3B(i)] with progressive reduction in signal over time [Fig. 3B(ii)] and the absence of teratomas in kidneys injected with either AdMSCs or iMS cells [Fig. 3B(iii)]. Injection of equivalent numbers of iPS cells and iPS + iMS cell mixtures (1:49) to approximate iMS fraction expressing pluripotency markers led to spontaneous tumor formation in the same timeframe [Fig. 3B(iii)].

(A) Generation of luciferase/GFP-reporter AdMSCs and iMS cells, and assessment of their in vivo function. (B) Assessment of teratoma initiating capacity; (i) bioluminescence images at 0, 2, 6, and 8 weeks after implantation of 1 106 matched AdMSCs and iMS cells (P2; RM0057; n = 2 per group) under the right kidney capsules. (ii) Quantification of bioluminescence. (iii) Gross kidney morphology 8 weeks following subcapsular implantation of cells (R) or vehicle control (L). (C) Assessment of in vivo plasticity in a posterior-lateral intertransverse lumbar fusion model; (i) bioluminescence images following lumbar implantation of 1 106 matched AdMSCs or iMS cells (P2; RM0038; n = 3 per group) at 1 and 365 days after transplant. (ii) Quantification of bioluminescence. (iii) Tissues (bone, cartilage, muscle, and blood vessels) harvested at 6 months after implantation stained with (left) hematoxylin and eosin or (right) lineage-specific anti-human antibodies circles/arrows indicate regions covering GFP and lineage markerpositive cells. Corresponding graphs show donor cell (GFP+) contributions to bone, cartilage, muscle, and blood vessels as a fraction of total (DAPI+) cells in four to five serial tissue sections. Bars indicate confidence interval, n = 3. Photo Credit: Avani Yeola, UNSW Sydney.

To evaluate whether iMS cells survived and integrated with damaged tissues in vivo, we implanted transduced human iMS cells and matched AdMSCs controls into a posterior-lateral intertransverse lumbar fusion mouse model (Fig. 3A) (29). Cells were loaded into Helistat collagen sponges 24 hours before implantation into the posterior-lateral gutters adjacent to decorticated lumbar vertebrae of NSG mice (n = 9 iMS and n = 9 AdMSC). Cell retention in situ was confirmed by intraperitoneal injection of d-luciferin (150 mg/ml) followed by BLI 24 hours after cell implantation, then weekly for the first 6 weeks and monthly up to 12 months from implantation [Fig. 3C(i)]. The BLI signal gradually decreased with time but persisted at the site of implantation at 12 months, the final assessment time point [Fig. 3C(ii)]. Groups of mice (n = 3 iMS and n = 3 AdMSC) were euthanized at 3, 6, and 12 months and tissues harvested from sites of cell implantation for histology and immunohistochemistry [Fig. 3C(iii)]. Although implanted iMS cells and AdMSCs were present and viable at sites of implantation at 3 months, there was no evidence of lineage-specific gene expression in donor human cells (fig. S5C). By contrast, at 6 months after implantation, GFP+ donor iMS cells and AdMSCs were shown to contribute to new bone (BMP2), cartilage (SOX9), muscle (MYH), and endothelium (CD31) at these sites of tissue injury [Fig. 3C(iii)]. The proportion of donor cells expressing lineage-specific markers in a corresponding tissue section was significantly higher in iMS cells compared with matched AdMSCs at 6 months [Fig. 3C(iii) and table S2] as well as 12 months (fig. S5, E and D, and table S2). There was no evidence of malignant growth in any of the tissue sections or evidence of circulating implanted GFP+ iMS cells or AdMSCs (fig. S5E). Together, these data show that implanted iMS cells were not teratogenic, were retained long term at sites of implantation, and contributed to regenerating tissues in a context-dependent manner with greater efficiency than matched AdMSCs.

Although appropriate to assess in vivo plasticity and teratogenicity of implanted cells, the posterior-lateral intertransverse lumber fusion mouse model is not suited to address the question of tissue-specific differentiation and repair in vivo. To this end, we used a muscle injury model (30) where necrosis was induced by injecting 10 M cardiotoxin (CTX) into the left tibialis anterior (TA) muscle of 3-month-old female severe combined immunodeficient (SCID)/Beige mice. CTX is a myonecrotic agent that spares muscle satellite cells and is amenable to the study of skeletal muscle regeneration. At 24 hours after injury, Matrigel mixed with either 1 106 iMS cells or matched AdMSCs (or no cells as a control) was injected into the damaged TA muscle. The left (injured) and right (uninjured control) TA muscles were harvested at 1, 2, or 4 weeks after injury to assess the ability of donor cells to survive and contribute to muscle regeneration without ectopic tissue formation (Fig. 4A; cohort A). Donor human iMS cells or AdMSCs compete with resident murine muscle satellite cells to regenerate muscle, and their regenerative capacity is expected to be handicapped not only by the species barrier but also by having to undergo muscle satellite cell commitment before productive myogenesis. Recognizing this, a cohort of mice was subject to a second CTX injection, 4 weeks from the first injury/cell implantation followed by TA muscle harvest 4 weeks later (Fig. 4A; cohort B).

(A) Generation of iMS and AdMSCs and their assessment in TA muscle injury model. (B) (i) Confocal images of TA muscle stained for human CD56+ satellite cells (red) and laminin basement membrane protein (green; mouse/human). Graph shows donor hCD56+ satellite cell fraction for each treatment group. (ii) Confocal images of TA muscle harvested at 4 weeks and stained for human spectrin (red) and laminin (green; mouse/human). For each treatment, the left panel shows a tile scan of the TA muscle and the right panel a high magnification confocal image. Graph shows contribution of mouse (M), human (H), or chimeric (C) myofibers in three to five serial TA muscle sections per mouse (n = 3 mice per treatment group). (C) Confocal images of TA muscle 4 weeks following re-injury with CTX, stained for human spectrin (red) and laminin (green; mouse/human). For each treatment, left panel shows a tile scan of the TA muscle, upper right panel a low-magnification image, and lower right panel a high magnification image of the area boxed above. Graph shows contribution of mouse (M), human (H), or chimeric (C) myofibers in three to five serial TA muscle sections per mouse (n = 3 mice per treatment group). Graph bars indicate confidence interval. *P < 0.05, **P < 0.01, and ***P < 0.001 (linear mixed model). Photo credit: Avani Yeola, UNSW Sydney.

In tissue sections harvested from cohort A, donor-derived muscle satellite cells (31) [hCD56 (Thermo Fisher Scientific, MA5-11563)+; red] were evident in muscles implanted with both iMS cells and AdMSCs at each time point but were most numerous at 2 weeks after implantation [Fig. 4B(i) and fig. S6A]. The frequency of hCD56+ cells relative to total satellite cells [sublaminar 4,6-diamidino-2-phenylindolepositive (DAPI+) cells] was quantified in three to five serial sections of TA muscles per mouse in each of three mice per treatment group and was noted to be higher following the implantation of iMS cells compared with AdMSCs at all time points [week 1, 5.6% versus 2.4%; week 2, 43.3% versus 18.2%; and week 4, 30.7% versus 14.6%; Fig. 4B(i), table S2, and fig. S6A]. Donor cell contribution to regenerating muscle fibers was also assessed by measuring human spectrin (32) costaining with mouse/human laminin [(33) at 4 weeks (Fig. 4B(ii)]. At least 1000 myofibers from three to five serial sections of TA muscles for each of three mice in each treatment group were scored for human [H; hSpectrin+ (full circumference); laminin+], murine (M; mouse; hSpectrin; laminin+), or mouse/human chimeric [C; hSpectrin+ (partial circumference); laminin+] myofibers. Although none of the myofibers seen in cross section appeared to be completely human (i.e., donor-derived), both iMS cells and AdMSCs contributed to chimeric myofibers [Fig. 4B(ii)]. iMS cell implants contributed to a substantially higher proportion of chimeric fibers than AdMSC implants (57.7% versus 30.7%; table S2). In cohort B, TA muscles were allowed to regenerate following the initial CTX injection/cell implantation, and re-injured 4 weeks later with a repeat CTX injection. In these mice, although total donor cell contributions to myofibers in TA muscles harvested 4 weeks after re-injury were comparable to that observed in cohort A, there were no myofibers that appeared to be completely human (Fig. 4C). There were substantially more human myofibers following iMS cell implants than with AdMSCs (9.7% versus 5.4%; table S2). There was no evidence of ectopic tissue formation in TA muscles following implantation of either iMS cells or AdMSCs in either cohort.

To assess the physiological properties of muscles regenerated with human myofibers, we performed tetanic force contractions in extensor digitorum longus (EDL) muscles following the schema shown in Fig. 4A. Tetanic forces evoked by electrical pulses of various stimulus frequencies were not significantly different between the experimental cohorts or between the experimental cohorts and control animals [fig. S6B, (i) to (iii)]. However, when challenged with a sustained train of electrical pulses [fig. S6C(i)], the iMS group demonstrated significantly greater absolute [fig. S6C(ii)] and specific [fig. S6C(iii)] forces over a 3- to 6-s period. Together, these data showed that iMS cells had the capacity to respond appropriately to the injured environment and contribute to tissue-specific regeneration without impeding function.

We have optimized a protocol, originally designed for mouse osteocytes, to convert human primary adipocytes into iMS cells. We show that these long-term repopulating cells regenerate tissues in vivo in a context-dependent manner without generating ectopic tissues or teratomas.

PDGF-AB, AZA, and serum are indispensable ingredients in reprograming media, but the underlying reasons for their cooperativity and the observed dose-response variability between patients are not known. PDGF-AB is reported to bind and signal via PDGFR- and PDGFR- but not PDGFR- subunits (21). Mouse osteocytes and human adipocytes lack PDGFR, although surface expression was detectable as cells transition during reprogramming [mouse; day 2 of 8 (14) and human day 21 of 25]. However, these cells express PDGFR (14). Given that PDGFR inhibition attenuates iMS cell production in both mice (14) and humans, a degree of facilitated binding of PDGF-AB to PDGF- subunits or signaling through a noncanonical receptor is likely to occur, at least at the start of reprogramming. PDGF-Bcontaining homo- and heterodimers are potent mitogens that increase the pool of undifferentiated fibroblasts and preosteoblasts with rhPDGF-BB used in the clinic to promote healing of chronic ulcers and bone regeneration (34). However, the unique characteristics of PDGF-AB but not PDGF-BB or PDGF-AA that facilitate reversal and plasticity of cell identity in combination with AZA and serum (14) remain unknown.

PDGF-AB was replenished in culture throughout the reprogramming period, but AZA treatment was limited to the first 2 days for both mouse osteocyte and human adipocyte cultures. DNA replication is required for incorporation of AZA into DNA (35) and hence DNA demethylation is unlikely to be an initiating event in the conversion of terminally differentiated nonproliferating cells such as osteocytes and mature adipocytes. However, the majority of intracellular AZA is incorporated into RNA, which could directly affect the cellular transcriptome and proteome as an early event (36, 37). It is feasible that subsequent redistribution of AZA from RNA to DNA occurs when cells replicate resulting in DNA hypomethylation as a later event (38).

In the absence of serum, we could neither convert primary human adipocytes into iMS cells nor perpetuate these cells long term in culture. The efficiency of conversion and expansion was significantly higher with human versus FCS and highest with AS. The precise serum factor(s) that are required for cell conversion in conjunction with PDGF-AB and AZA are not known. The volumes of blood (~50 ml 2) and subcutaneous fat (5 g) that we harvested from donors were not limiting to generate sufficient numbers of P2 iMS cells (~10 106) for in vivo implantation and are in the range of cell numbers used in prospective clinical trials using mesenchymal precursor cells for chronic discogenic lumbar back pain (NCT02412735; 6 106) and hypoplastic left heart syndrome (NCT03079401; 20 106).

Our motivation was to optimize a protocol that could be applied to primary uncultured and easily accessible cells for downstream therapeutic applications, and adipose tissue satisfied these criteria. We have not surveyed other human cell types for their suitability for cell conversion using this protocol. It would be particularly interesting to establish whether tissue-regenerative properties of allogeneic mesenchymal precursor populations that are currently in clinical trials could be boosted by exposure to PDGF-AB/AZA. However, given that iMS cells and MSCs share stromal cell characteristics, identifying a unique set of cell surface markers that can distinguish the former is a priority that would assist in future protocol development and functional assessment of iMS cells.

Producing clinical-grade autologous cells for cell therapy is expensive and challenging requiring suitable quality control measures and certification. However, the advent of chimeric antigen receptor T cell therapy into clinical practice (39) has shown that production of a commercially viable, engineered autologous cellular product is feasible where a need exists. Although there were no apparent genotoxic events in iMS cells at P2, ex vivo expansion of cells could risk accumulation of such events and long-term follow-up of ongoing and recently concluded clinical trials using allogeneic expanded mesenchymal progenitor cells will be instructive with regard to their teratogenic potential. The biological significance of the observed expression of pluripotency-associated transcription factors in 2 to 3% of murine and human iMS cells is unknown and requires further investigation. However, their presence did not confer teratogenic potential in teratoma assays or at 12-month follow-up despite persistence of cells at the site of implantation. However, this risk cannot be completely discounted, and the clinical indications for iMS or any cell therapy require careful evaluation of need.

In regenerating muscle fibers, it was noteworthy that iMS cells appeared to follow canonical developmental pathways in generating muscle satellite cells that were retained and primed to regenerate muscle following a second muscle-specific injury. Although iMS cells were generated from adipocytes, there was no evidence of any adipose tissue generation. This supports the notion that these cells have lost their native differentiation trajectory and adopted an epigenetic state that favored response to local differentiation cues. The superior in vivo differentiation potential of iMS cells vis--vis matched AdMSCs was consistent with our data showing that despite the relatively minor transcriptomic differences between these cell types, the epigenetic state of iMS cells was better primed for systems development. Another clear distinction between iMS cells and AdMSCs was the ability of the former to produce CD31+ endothelial tube-like structures that were enveloped by PDGFR+ pericytes. An obvious therapeutic application for iMS cells in this context is vascular regeneration in the setting of critical limb ischemia to restore tissue perfusion, an area of clear unmet need (40).

An alternative to ex vivo iMS cell production and expansion is the prospect of in situ reprogramming by local subcutaneous administration of the relevant factors to directly convert subcutaneous adipocytes into iMS cells, thereby eliminating the need for ex vivo cell production. AZA is used in clinical practice and administered as a daily subcutaneous injection for up to 7 days in a 28-day cycle, with responders occasionally remaining on treatment for decades (41). Having determined the optimal dose of AZA required to convert human adipocytes into iMS cells in vitro (2 days, 5 M), the bridge to ascertaining the comparable in vivo dose would be to first measure levels of AZA incorporation in RNA/DNA following in vitro administration and match the dose of AZA to achieve comparable tissue levels in vivo. A mass spectrometrybased assay was developed to measure in vivo incorporation of AZA metabolites (AZA-MS) in RNA/DNA and is ideally suited to this application (38). The duration of AZA administration for adipocyte conversion was relatively short (i.e., 2 days), but PDGF-AB levels were maintained for 25 days. One mechanism of potentially maintaining local tissue concentrations would be to engineer growth factors to bind extra cellular matrices and be retained at the site of injection. Vascular endothelial growth factor A (VEGF-A) and PDGF-BB have recently been engineered with enhanced syndecan binding and shown to promote tissue healing (42). A comparable approach could help retain PDGF-AB at the site of injection and maintain local concentrations at the required dose. While our current data show that human adipocytederived iMS cells regenerate tissues in a context-dependent manner without ectopic or neoplastic growth, these approaches are worth considering as an alternative to an ex vivo expanded cell source in the future.

Extended methods for cell growth and differentiation assays and animal models are available in the Supplementary Materials, and antibodies used are detailed in the relevant sections.

The primary objective of this study was to optimize conditions that were free of animal products for the generation of human iMS cells from primary adipocytes and to characterize their molecular landscape and function. To this end, we harvested subcutaneous fat from donors across a broad age spectrum and used multiple dose combinations of a recombinant human growth factors and a hypomethylating agent used in the clinic and various serum types. We were particularly keen to demonstrate cell conversion and did so by live imaging and periodic flow cytometry for single-cell quantification of lipid loss and gain of stromal markers. Using our previous report generating mouse iMS cells from osteocytes and adipocytes as a reference, we first characterized the in vitro properties of human iMS cells including (i) long-term growth, (ii) colony-forming potential, (iii) in vitro differentiation, and (iv) molecular landscape. Consistent with their comparative morphology, cell surface markers, and behavioral properties, the transcriptomes (RNA sequencing) were broadly comparable between iMS cells and matched AdMSCs, leading to investigation of epigenetic differences [Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) histone chromatin immunoprecipitation sequencing (ChIP-seq), and RRBS for DNA methylation differences] that might explain properties that were unique to iMS cells (expression of pluripotency factors, generation of endothelial tubes in vitro with pericyte envelopes, and in vivo regenerative potential). Context-dependent in vivo plasticity was assessed using a tissue injury model that was designed to promote bone/cartilage/muscle/blood vessel contributions from donor cells and simultaneously assess the absence of ectopic/malignant tissue formation by these cells (labeled and tracked in vivo using a bioluminescence/fluorescence marker). Tissue-specific regeneration and the deployment of canonical developmental pathways were assessed using a specific muscle injury model, and donor cell contributions in all injury models were performed on multiple serial tissue sections in multiple mice with robust statistical analyses (see below). Power calculations were not used, samples were not excluded, and investigators were not blinded. Experiments were repeated multiple times or assessments were performed at multiple time points. Cytogenetic and Copy Number Variation (CNV) analyses were performed on iMS and AdMSCs pretransplant, and their teratogenic potential was assessed both by specific teratoma assays and long-term implantation studies.

Subcutaneous fat and blood were harvested from patients undergoing surgery at the Prince of Wales Hospital, Sydney. Patient tissue was collected in accordance with National Health and Medical Research Council (NHMRC) National Statement on Ethical Conduct in Human Research (2007) and with approval from the South Eastern Sydney Local Health District Human Research Ethics Committee (HREC 14/119). Adipocytes were harvested as described (43). Briefly, adipose tissue was minced and digested with 0.2% collagenase type 1 (Sigma-Aldrich) at 37C for 40 min and the homogenized suspension passed through a 70-m filter, inactivated with AS, and centrifuged. Primary adipocytes from the uppermost fatty layer were cultured using the ceiling culture method (44) for 8 to 10 days. AdMSCs from the stromal vascular pellet were cultured in MEM + 20% AS + penicillin (100 g/ml) and streptomycin (250 ng/ml), and 200 mM l-glutamine (complete medium).

Adherent mature adipocytes were cultured in complete medium supplemented with AZA (R&D systems; 5, 10, and 20 M; 2 days) and rhPDGF-AB (Miltenyi Biotec; 100, 200, and 400 ng/ml; 25 days) with medium changes every 3 to 4 days. For inhibitor experiments, AG1296 was added for the duration of the culture. Live imaging was performed using an IncuCyte S3 [10 0.25numerical aperture (NA) objective] or a Nikon Eclipse Ti-E (20 0.45-NA objective). Images were captured every 30min for a period of 8 days starting from day 15. Twelve-bit images were acquired with a 1280 1024 pixel array and analyzed using ImageJ software. In vitro plasticity was determined by inducing the cells to undergo differentiation into various cell types using differentiation protocols adapted from a previous report (45).

Animals were housed and bred with approval from the Animal Care and Ethics Committee, University of New South Wales (UNSW; 17/30B, 18/122B, and 18/134B). NSG (NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ) and SCID/Beige (C.B-Igh-1b/GbmsTac-Prkdcscid-Lystbg N, sourced from Charles River) strains were used as indicated. The IVIS Spectrum CT (Perkin Elmer) was used to capture bioluminescence. Briefly, 15 min after intraperitoneal injection of d-luciferin (150 mg/kg), images were acquired for 5 min and radiance (photon s1 cm2 sr1) was used for subsequent data analysis. The scanned images were analyzed using the Living Image 5.0 software (Perkin Elmer).

Teratoma assays (46) were performed on 3- to 4-month-old female NSG mice. Lentiviral-tagged cells (5 105) in 20 l of phosphate-buffered saline containing 80% Matrigel were injected under the right kidney capsule using a fine needle (26 gauges) and followed weekly by BLI until sacrifice at week 8. Both kidneys were collected, fixed in 4% paraformaldehyde (PFA) for 48 hours, embedded in optimal cutting temperature compound (OCT), cryosectioned, and imaged for GFP.

Posterior-lateral intervertebral disc injury model (29). Lentiviral-tagged (28) AdMSCs (1 106) or iMS cells were loaded onto Helistat collagen sponges and implanted into the postero-lateral gutters in the L4/5 lumbar spine region of anesthetized NSG mice following decortication of the transverse processes. Animals were imaged periodically for bioluminescence to track the presence of transplanted cells. At 3, 6, or 12 months, mice were euthanized, and spines from the thoracic to caudal vertebral region, including the pelvis, were removed whole. The specimens were fixed in 4% PFA for 48 hours, decalcified in 14% (w/v) EDTA, and embedded in OCT.

Muscle injury model (47). The left TA and EDL muscles of 3- to 4-month-old female SCID/Beige mice were injured by injection with 15 l of 10 M CTX (Latoxan). Confocal images of three to four serial sections (TA) per mouse were captured by Zen core/AxioVision (Carl Zeiss) and visualized by ImageJ with the colocalization and cell counter plugins [National Institutes of Health; (48)]. Tetanic force contractions were performed on EDL muscles (49).

Total RNA was extracted using the miRNeasy Mini Kit (Qiagen) according to manufacturers instructions, and 200 ng of total RNA was used for Illumina TruSeq library construction. Library construction and sequencing was performed by Novogene (HK) Co. Ltd. Raw paired-end reads were aligned to the reference genome (hg19) using STAR (https://github.com/alexdobin/STAR), and HTSeq (50) was used to quantify the transcriptomes using the reference refFlat database from the UCSC Table Browser (51). The resulting gene expression matrix was normalized and subjected to differential gene expression using DeSeq2 (52). Normalized gene expression was used to compute and plot two-dimensional principal components analysis, using the Python modules sklearn (v0.19.1; https://scikit-learn.org/stable/) and Matplotlib (v2.2.2; https://matplotlib.org/), respectively. Differentially expressed genes (log2 fold change |1|, adjusted P < 0.05) were the input to produce an unsupervised hierarchical clustering heat map in Partek Genomics Suite software (version 7.0) (Partek Inc., St. Louis, MO, USA). Raw data are available using accession GSE150720.

ChIP was performed as previously described (53) using antibodies against H3K27Ac (5 g per IP; Abcam, ab4729), H3K4Me3 (5 g per IP; Abcam ab8580), and H3K27Me3 (5 g per IP; Diagenode, C15410195). Library construction and sequencing were performed by Novogene (HK) Co. Ltd. Paired-end reads were aligned to the hg38 genome build using Burrows Wheeler Aligner (BWA) (54) duplicate reads removed using Picard (http://broadinstitute.github.io/picard/), and tracks were generated using DeepTools bamCoverage (https://deeptools.readthedocs.io/en/develop/). Peaks were called using MACS2 (55) with the parameter (P = 1 109). Differentially bound regions between the AdMSC and iMS were calculated using DiffBind (http://bioconductor.org/packages/release/bioc/vignettes/DiffBind/inst/doc/DiffBind.pdf) and regions annotated using ChIPseeker (56). Raw data are available using accession GSE151527. Adipocyte ChIP data were downloaded from Gene Expression Omnibus (GEO); accession numbers are as follows for the three histone marks: GSM916066, GSM670041, and GSM772771.

Total genomic DNA was extracted using the DNA MiniPrep Kit (Qiagen), and RRBS library construction and sequencing were performed by Novogene (HK) Co. Ltd. Raw RRBS data in fastq format were quality and adapter trimmed using trim_galore (0.6.4) with rrbs parameter (www.bioinformatics.babraham.ac.uk/projects/trim_galore). The trimmed fastq files were then aligned to a bisulfite-converted genome (Ensembl GRCh38) using Bismark (2.3.5), and methylation status at each CpG loci was extracted (57). The cytosine coverage files were converted to BigWig format for visualization. Differentially methylated cytosines (DMCs) and DMRs were identified using methylKit (1.10) and edmr (0.6.4.1) packages in R (3.6.1) (58, 59). DMCs and DMRs were annotated using ChIPseeker (56), and pathway enrichment was performed as detailed below. Raw data are available using accession number GSE151527. Adipocyte RRBS data were downloaded from GEO: GSM2342293 and GSM2342392.

IPA (Qiagen) was used to investigate enrichment in molecular and cellular functions, systems development and function, and canonical pathways.

Statistical analysis was performed in SAS. For the dose-optimization experiments (Fig. 1), a linear mixed model with participant-level random effects was used to estimate maximum time by dose level and age group. A linear mixed model with participant-level random effects was used to analyze statistical differences in lineage contribution outcomes between treatment groups (Fig. 3) and at different time points posttransplant, to estimate the percentage of cells by treatment and lineage. For the in vivo regeneration experiment (Fig. 4), a linear model was used to model the percent of cells over time for each group. Quadratic time terms were added to account for the observed increase from 1 to 2 weeks and decrease from 2 to 4 weeks. In the muscle regeneration experiment, a linear model was applied to cohort A and cohort B, to estimate and compare percent cells by treatment and source. Statistical modeling data are included in table S2.

Acknowledgments: We are indebted to the patients who donated tissue to this project. We thank E. Cook (Prince of Wales Private Hospital), B. Lee (Mark Wainwright Analytical Centre, UNSW Sydney), and technicians at the UNSW BRC Facility for assistance with sample and data collection and animal care; Y. Huang for technical assistance; and A. Unnikrishnan and C. Jolly for helpful discussions and critical reading of the manuscript. We acknowledge the facilities and scientific and technical assistance of the National Imaging Facility, a National Collaborative Research Infrastructure Strategy (NCRIS) capability, at the BRIL (UNSW). The STRO-1 antibody was a gift from S. Gronthos, University of Adelaide, Australia. Funding: We acknowledge the following funding support: A.Y. was supported by an Endeavour International Postgraduate Research scholarship from the Australian Government. S.S. is supported by an International Postgraduate Student scholarship from UNSW and the Prince of Wales Clinical School. P.S. is supported by an International Postgraduate Student scholarship from UNSW. M.L.T. and D.D.M. acknowledge funding from St. Vincents Clinic Foundation and Arrow BMT Foundation. K.A.K. acknowledges funding from Australian Research Council (FT180100417). J.M. is supported, in part, by the Olivia Lambert Foundation. M.K. is supported by a NHMRC Program Grant (APP1091261) and NHMRC Principal Research Fellowship (APP1119152). L.B.H. acknowledges funding from MTPConnect MedTech and Pharma Growth Centre (PRJ2017-55 and BMTH06) as part of the Australian Governmentfunded Industry Growth Centres Initiative Programme and The Kinghorn Foundation. D.B. is supported by a Peter Doherty Fellowship from the National Health and Medical Research Council of Australia, a Cancer Institute NSW Early Career Fellowship, the Anthony Rothe Memorial Trust, and Gilead Sciences. R.M. acknowledges funding from Jasper Medical Innovations (Sydney, Australia). J.E.P., V.C., and E.C.H. acknowledge funding from the National Health and Medical Research Council of Australia (APP1139811). Author contributions: The project was conceived by V.C. and J.E.P., and the study design and experiments were planned by A.Y., V.C., and J.E.P. Most of the experiments and data analyses were performed by A.Y., guided and supervised by V.C. and J.E.P. S.S., R.A.O., C.A.L., D.C., F.Y., M.L.T., P.S., T.H., J.R.P., P.H., W.R.W., and V.C. performed additional experiments and data analyses, with further supervision from R.M., C.P., J.A.I.T., D.C., J.W.H.W., L.B.H., D.B., and E.C.H. Statistical analyses were performed by J.O. R.M., D.D.M., J.M., K.A.K., and M.K. provided critical reagents. The manuscript was written by A.Y., J.A.I.T., V.C., and J.E.P., and reviewed and agreed to by all coauthors. Competing interests: V.C. and J.E.P. are named inventors on a patent A method of generating cells with multi-lineage potential (US 9982232, AUS 2013362880). All other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Induction of muscle-regenerative multipotent stem cells from human adipocytes by PDGF-AB and 5-azacytidine - Science Advances

IPS Cell Therapy Comments Off on Induction of muscle-regenerative multipotent stem cells from human adipocytes by PDGF-AB and 5-azacytidine – Science Advances | January 14th, 2021

After 15 years of unrelenting work, a team of scientists from Gladstone Institutes has now discovered a potential drug candidate for heart valve disease that works in both human cells and animals and is ready to move toward a clinical trial. Their findings were just published in the journal Science.

"The disease is often diagnosed at an early stage and calcification of the heart valves worsens over the patient's lifetime as they age," says Gladstone President and Director of the Roddenberry Stem Cell Center Deepak Srivastava, MD,who led the study. "If we could intervene early in life with an effective drug, we could potentially prevent the disease from occurring. By simply slowing the progression and shifting the age of people who require interventions by 5 or 10 years, we could avoid tens of thousands of surgical valve replacements every year."

This also applies to the millions of Americansabout one to two percent of the populationwith a congenital anomaly called bicuspid aortic valve, in which the aortic valve only has two leaflets instead of the normal three. While some people may not even know they have this common heart anomaly, many will be diagnosed as early as their forties.

"We can detect this valve anomaly through an ultrasound," explains Srivastava, who is also a pediatric cardiologist and a professor in the Department of Pediatrics at UC San Francisco (UCSF). "About a third of patients with bicuspid aortic valve, which is a very large number, will develop enough calcification to require an intervention."

Srivastava's research into heart valve disease started in 2005, when he treated a family in Texas who had this type of early-onset calcification. All these years later, thanks to the family's donated cells, his team has finally found a solution to help them and so many others.

A Holistic Approach in the Hunt for a Therapy

Members of the family treated by Srivastava had disease that crossed five generations, enabling the team to identify the causea mutation in one copy of the gene NOTCH1. Mutations in this gene cause calcific aortic valve disease in approximately four percent of patients and can also cause thickening of valves that trigger problems in newborns. In the other 96 percent of cases, the disease occurs sporadically.

"The NOTCH1 mutation provided a foothold for us to figure out what goes wrong in this common disease, but most people won't have that mutation," says Srivastava. "However, we found that the process that leads to the calcification of the valve is mostly the same whether individuals have the mutation or not. The valve cells get confused and start thinking they're bone cells, so they start laying down calcium and that leads to hardening and narrowing of the valves."

In the hunt for a treatment, the group of scientists chose a novel, holistic approach rather than simply focusing on a single target, such as the NOTCH1 gene.

"Our goal was to develop a new framework to discover therapeutics for human disease," says Christina V. Theodoris, MD, PhD, lead author of the study who is now completing her residency in pediatric genetics at Boston Children's Hospital. "We wanted to find promising therapies that could treat the disease at its core, as opposed to just treating some specific symptoms or peripheral aspects of the disease."

When Theodoris first joined Srivastava's lab at Gladstone, she was a graduate student at UCSF. At the time, they knew the NOTCH1 gene mutation caused valve disease, but they didn't have the tools to study the problem further, largely because it was very difficult to obtain valve cells from patients.

"My first project was to convert the cells from the patient families into induced pluripotent stem (iPS) cells, which have the potential of becoming any cell in the body, and turn them into cells that line the valve, allowing us to understand why the disease occurs," says Theodoris. "My second project was to make a mouse model of calcific aortic valve disease. Only then could we start using these models to identify a therapy."

One Drug Candidate Rises to the Top

For this latest study, the scientists searched for drug-like molecules that could correct the overall network that goes awry in heart valve disease and leads to calcification. To do so, they first had to determine the network of genes that are turned on or off in diseased cells.

Then, they used an artificial intelligence method, training a machine learning program to detect whether a cell was healthy or sick based on this network of genes. They subsequently treated diseased human cells with nearly 1,600 molecules to see if any drugs shifted the network in the cells enough that the machine learning program would reclassify them as healthy. The researchers identified a few molecules that could correct diseased cells back to the normal state.

"Our first screen was done with cells that have the NOTCH1 mutation, but we didn't know if the drugs would work on the other 96 percent of patients with the disease," says Srivastava.

Fortunately, Anna Malashicheva, PhD, from the Russian Academy of Sciences, had collected valve cells from over 20 patients at the time of surgical replacement, and Srivastava struck up a fruitful collaboration with her group to do a "clinical trial in a dish."

"We tested the promising molecules on cells from these 20 patients with aortic valve calcification without known genetic causes," Srivastava adds. "Remarkably, the molecule that seemed most effective in the initial study was able to restore the network in these patients' cells as well."

Once they had identified a promising candidate in cells in a dish for both NOTCH1 and sporadic cases of calcific aortic valve disease, Srivastava and his team did a "pre-clinical trial" in a mouse model of the disease. They wanted to determine whether the drug-like molecule would actually work in a whole, living organ.

The scientists confirmed that the therapeutic candidate could successfully prevent and treat aortic valve disease. In young mice who had not yet developed the disease, the therapy prevented the calcification of the valve. And in mice that already had the disease, the therapy actually halted the disease and, in some cases, led to reversal of the disease. This finding is especially important since most patients aren't diagnosed until calcification has already begun.

"Our strategy to identify gene networkcorrecting therapies that treat the core disease mechanism may represent a compelling path for drug discovery in a range of other human diseases," says Theodoris. "Many therapeutics found in the lab don't translate well to humans or focus only on a specific symptom. We hope our approach can offer a new direction that could increase the likelihood of candidate therapies being effective in patients."

The researchers' strategy relied heavily on technological advancements, including human iPS cells, gene editing, targeted RNA sequencing, network analysis, and machine learning.

"Our study is a really good example of how modern technologies are facilitating the kinds of discoveries that are possible today, but weren't not so long ago," says Srivastava. "Using human iPS cells and gene editing allowed us to create a large number of cells that are relevant to the disease process, while powerful machine learning algorithms helped us identify, in a non-biased fashion, the important genes for distinguishing between healthy and diseased cells."

"By using all the knowledge we gathered over a decade and a half, combined with the latest tools, we were able to find a drug candidate that can be taken to clinical trials," he adds. "Our ultimate goal is always to help patients, so the whole team is very pleased that we found a therapy that could truly improve lives."

About the Research Project

The paper, "Network-based screen in iPSC-derived cells reveals therapeutic candidate for heart valve disease,"was published online by Science on December 10, 2020.

Other authors include Ping Zhou, Lei Liu, Yu Zhang, Tomohiro Nishino, Yu Huang, Sanjeev S. Ranade, Casey A. Gifford, Sheng Ding from Gladstone; Aleksandra Kostina from the Russian Academy of Sciences; and Vladimir Uspensky from the Almazov Federal Medical Research Centre in Russia.

The work was funded by the California Institute of Regenerative Medicine; the National Heart, Lung, and Blood Institute; and the National Center for Research Resources. Gladstone researchers also received support from the Winslow Family, the L.K. Whittier Foundation, The Roddenberry Foundation, the Younger Family Fund, the American Heart Association, several programs and fellowships at UCSF, residency programs from Boston Children's Hospital and the Harvard Medical School, the Uehara Memorial Foundation, and a Howard Hughes Medical Institute Fellowship of the Damon Runyon Cancer Research Foundation.

About Gladstone Institutes

To ensure our work does the greatest good, Gladstone Institutes focuses on conditions with profound medical, economic, and social impactunsolved diseases. Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease.

Media Contact: Julie Langelier | Assistant Director, Communications | [emailprotected] | 415.734.5000

SOURCE Gladstone Institutes

https://gladstone.org

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A Potential Therapy for One of the Leading Causes of Heart Disease - PRNewswire

IPS Cell Therapy Comments Off on A Potential Therapy for One of the Leading Causes of Heart Disease – PRNewswire | December 10th, 2020

HAMBURG, GERMANY / ACCESSWIRE / December 9, 2020 / Evotec SE (Frankfurt Stock Exchange: EVT, MDAX/TecDAX, ISIN: DE0005664809) and the life science company Sartorius announced today that they have entered into a partnership with the recently established Curexsys GmbH, a Goettingen, Germany-based technology leader specialising in the emerging field of therapeutic exosomes.

Curexsys delivers a proprietary isolation technology for exosomes based on a traceless immune-affinity process. This process is different from commonly used antibody-based processes and enables the company to overcome a key hurdle in exosome preparation, i.e. remaining antibodies in the final preparation. Curexsys is founded by Herbert Stadler, a serial biotech entrepreneur, and Jens Gruber, a former group leader of Medical RNA Biology who is going to lead Curexsys as Chief Scientific Officer.

Under the terms of the agreement, Evotec and Curexsys will collaborate with the production of Human Mesenchymal Stem Cells ("MSCs"), which serve as a source for exosomes. These are small vesicles that are naturally released from a cell. They contain proteins, nucleic acids and metabolites, which carry information from secreting to receiving cells. Exosomes have immunomodulatory and anti-inflammatory effects, which makes them a promising novel approach for innovative regenerative therapies, as therapeutics in age-related conditions, but also for diagnostic purposes. Curexsys aims to develop targeted approaches for a variety of diseases, initially focusing on Sicca Syndrome, commonly known as "dry eye", an inflammatory condition affecting 14% to 17% of the adult population for whom there is currently no effective treatment available.

The collaboration combines Evotec's industry-leading induced Pluripotent Stem Cell ("iPSC") platform with Curexsys' proprietary technology to selectively isolate exosomes. Sartorius will support Curexsys to set up a GMP-compliant and scalable manufacturing platform.

Furthermore, Evotec and Sartorius have formed a consortium to jointly invest in Curexsys' 8.2 m seed financing round with Evotec acquiring an equity stake of approx. 37% in Curexsys and Sartorius of approx. 21%.

Dr Cord Dohrmann, Chief Scientific Officer of Evotec, commented: "Therapeutic exosomes hold significant promise for regenerative medicine and beyond. Steadily increasing evidence suggests that exosomes derived from stem cells can aid tissue repair and engineering vesicles could carry drugs to diseased tissues. These efforts have been held back by a dearth of standardised methods to isolate and study vesicles. Combining Evotec's industrial-grade iPSC and PanOmics platforms with Curexsys' proprietary exosome isolation technology and Sartorius' ability to translate these into a fully GMP-compliant process is a unique opportunity to build the leading exosome company in the industry."

Dr Ren Faber, Head of Sartorius' Bioprocess Solutions Division, said: "With our integrated portfolio of manufacturing solutions Sartorius is the 'go-to' partner for developers of such new modalities when it comes to implementing GMP-compliant, flexible production processes. We are very much looking forward to contributing our proven and scalable technology platform to Curexsys process and help them achieve their next milestones faster."

Dr Jens Gruber, Chief Scientific Officer of Curexsys, added: "We are very happy that we were able to form such a consortium with industry leaders in their field. This unique constellation gives Curexsys an optimal starting position to advance our technologies for highly specific isolation of exosomes and to rapidly approach therapeutic applications."

About Exosomes and CurexsysExosomes are extracellular, nanoscale vesicles that are actively secreted from cells to transfer information to neighbouring cells and distant tissues. Exosomes carry information of secreting to receiving cells utilising proteins, nucleic acids and metabolites. MSC-derived exosomes function as paracrine mediators that limit inflammation, reprogram immune cells, and activate endogenous repair pathways, recapitulating to a large extent the therapeutic effects of parental MSCs. Exosomes hold potential as diagnostics, as therapeutics and cosmeceuticals. More than 100 clinical trials involving exosomes are currently ongoing, demonstrating their broad therapeutic potential.

Curexsys is a Goettingen, Germany-based start-up company founded by molecular biologist Dr Jens Gruber and the biochemist and serial entrepreneur Dr Herbert Stadler. With a scalable and semi-automated proprietary system for traceless immune-affinity cell sorting, Curexsys aims to become the leading supplier for clinical grade exosomes in regenerative medicine and anti-aging therapies.

About Evotec and iPSCInduced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from adult cells. Pluripotent stem cells hold great promise in the field of regenerative medicine. Because they can propagate indefinitely, as well as give rise to every other cell type in the body (such as neurons, heart, pancreatic and liver cells), they represent a single source of cells that could be used to replace those lost to damage or disease.

Evotec has built an industrialised iPSC infrastructure that represents one of the largest and most sophisticated iPSC platforms in the industry. Evotec's iPSC platform has been developed over the last years with the goal to industrialise iPSC-based drug screening in terms of throughput, reproducibility and robustness to reach the highest industrial standards, and to use iPSC-based cells in cell therapy approaches via the Company's proprietary EVOcells platform.

ABOUT SARTORIUSThe Sartorius Group is a leading international partner of life science research and the biopharmaceutical industry. With innovative laboratory instruments and consumables, the Group's Lab Products & Services Division concentrates on serving the needs of laboratories performing research and quality control at pharma and biopharma companies and those of academic research institutes. The Bioprocess Solutions Division with its broad product portfolio focusing on single-use solutions helps customers to manufacture biotech medications and vaccines safely and efficiently. The Group has been annually growing by double digits on average and has been regularly expanding its portfolio by acquisitions of complementary technologies. In fiscal 2019, the company earned sales revenue of some 1.83 billion euros. At the end of 2019, more than 9,000 people were employed at the Group's approximately 60 manufacturing and sales sites, serving customers around the globe.

SARTORIUS CONTACTPetra KirchhoffHead of Corporate Communications and Investor Relations+49 (0)551.308.3684 petra.kirchhoff@sartorius.comwww.sartorius.com

ABOUT EVOTEC SEEvotec is a drug discovery alliance and development partnership company focused on rapidly progressing innovative product approaches with leading pharmaceutical and biotechnology companies, academics, patient advocacy groups and venture capitalists. We operate worldwide and our more than 3,400 employees provide the highest quality stand-alone and integrated drug discovery and development solutions. We cover all activities from target-to-clinic to meet the industry's need for innovation and efficiency in drug discovery and development (EVT Execute). The Company has established a unique position by assembling top-class scientific experts and integrating state-of-the-art technologies as well as substantial experience and expertise in key therapeutic areas including neuronal diseases, diabetes and complications of diabetes, pain and inflammation, oncology, infectious diseases, respiratory diseases, fibrosis, rare diseases and women's health. On this basis, Evotec has built a broad and deep pipeline of more than 100 co-owned product opportunities at clinical, pre-clinical and discovery stages (EVT Innovate). Evotec has established multiple long-term alliances with partners including Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CHDI, Novartis, Novo Nordisk, Pfizer, Sanofi, Takeda, UCB and others. For additional information please go to http://www.evotec.com and follow us on Twitter @Evotec.

FORWARD LOOKING STATEMENTSInformation set forth in this press release contains forward-looking statements, which involve a number of risks and uncertainties. The forward-looking statements contained herein represent the judgement of Evotec as of the date of this press release. Such forward-looking statements are neither promises nor guarantees, but are subject to a variety of risks and uncertainties, many of which are beyond our control, and which could cause actual results to differ materially from those contemplated in these forward-looking statements. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any such statements to reflect any change in our expectations or any change in events, conditions or circumstances on which any such statement is based.

SOURCE: Evotec AG via EQS Newswire

View source version on accesswire.com:https://www.accesswire.com/620112/Evotec-and-Sartorius-Partner-with-Start-Up-Curexsys-on-IPSC-Based-Therapeutic-Exosome-Approach

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Evotec and Sartorius Partner with Start-Up Curexsys on IPSC-Based Therapeutic Exosome Approach - BioSpace

IPS Cell Therapy Comments Off on Evotec and Sartorius Partner with Start-Up Curexsys on IPSC-Based Therapeutic Exosome Approach – BioSpace | December 9th, 2020

Since the discovery of induced pluripotent stem cells (iPSCs) in 2006, a large and thriving research products market has emerged, largely because the cells are non-controversial and can be generated directly from adult cells. It is clear that iPSCs represent a lucrative market segment, because methods for commercializing this cell type are expanding every year and clinical studies investigating iPSCs are swelling in number.

Therapeutic applications of iPSCs are also emerging. In 2013, RIKEN launched the worlds first study of an iPSC-derived cell therapy product, treating the first patient in 2014 with iPS cell-derived retinal sheets.Numerous studies with iPSCs have also been undertaken in Japan, with iPSC-derived treatments being used for the treatment of Parkinsons disease, heart disease, spinal cord injury, and platelet production.

In a world-first achieved in 2016, Cynata Therapeutics received approval to launch the worlds first formal trial of an allogeneic iPSC-derived cell product (CYP-001) for the treatment of GvHD. Riding the momentum within the CAR-T field, Fate Therapeutics is developing FT819, its off-the-shelf iPSC-derived CAR-T cell product candidate.

While the therapeutic progress is exciting, other methods of commercializing iPS cells have also expanded exponentially.

Since the discovery of iPSC technology nearly 15 years ago, exponential progress has been made in stem cell biology and regenerative medicine.

New pathological mechanisms have been identified and explained, new drugs identified by iPSC screens are in the pipeline, and the first clinical trials employing human iPSC-derived cell types have been initiated.

What do you think the next 15 years will hold? Let us know in the comments below.

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Induced Pluripotent Stem Cell (iPS Cell) Applications in 2020

IPS Cell Therapy Comments Off on Induced Pluripotent Stem Cell (iPS Cell) Applications in 2020 | November 28th, 2020

Introduction

An increasing number of patients with end-stage renal failure are undergoing dialysis therapy worldwide. It causes both medical and medicoeconomic problems. Renal transplantation has proven a successful therapy for most patients with end-stage renal failure, as the therapy results in a significant improvement in the patients quality of life, prolongs survival and is considered cost-effective [1]. However, the annual increase in the number of new patients with end-stage renal disease who need a renal transplant, and the widening gap between the demand for and the supply of donor kidneys have led to a progressive shortage of donor organs for transplant. This has become a serious issue and is worsened by the problem of limited graft survival due to immune rejection [1].

Among the strategies to overcome these problems is kidney regeneration using stem cells. Stem cells may be divided into two large categories: organ-specific or somatic stem cells and pluripotent stem cells. In contrast to organ-specific stem cells that generally have a limited potential for growth and differentiation, pluripotent stem cells, such as embryonic stem cells (ESCs) [24] and induced pluripotent stem (iPS) cells [57], have a virtually unlimited replicative capacity on culture dishes and are theoretically able to give rise to any cell type in the body. Stem cells have increasingly been used as a model system for understanding developmental mechanisms. In addition, in vitro culture and differentiation of stem cells offer unique opportunities for disease modeling, drug discovery, toxicology and cell replacement therapy [8]. The generation of specific functional cell types from ESCs has been demonstrated, including neural cells (several kinds of neuron and glia), vascular endothelia and smooth muscle, cardiomyocytes, hematopoietic cells, pancreatic insulin-producing cells and hepatocyte-like cells [8]. However, the protocol for in vitro differentiation of pluripotent stem cells into renal lineage cells has not been fully established.

Other approaches to regenerate kidney have also been investigated using organ-specific local stem cells within the kidney and bone marrow-derived hematopoietic stem cells [9]. Kidney regeneration using mesenchymal stem cells localized in bone marrow has also been examined [10]. However, the approaches are still being developed and the role of these stem cells in kidney regeneration remains to be well defined.

Therapeutic approaches using human ESCs face two major problems. One is the ethical issue derived from the use of human fertilized eggs, and the other is immune rejection in any cell or tissue transplantation due to histocompatibility antigenic differences between ESCs and patients. These problems have been overcome by a breakthrough experiment by Takahashi and Yamanaka. They identified four factors normally found in ESCs, Oct3/4, Sox2, c-Myc and Klf4, that were sufficient to reprogram both mouse and human somatic cells to closely resemble mouse and human ESCs [57]. They named these iPS cells. Since iPS cells can be generated from somatic cells of patients, clinical approaches using iPS cells are not associated with the two above problems (use of human fertilized egg and immune rejection). In the next natural step after iPS cell creation, significant progress has been made in redifferentiating iPS cells into somatic cells. As is the case with ESCs, iPS cells have been redifferentiated into several somatic tissues, including active motor neurons [11], insulin-secreting islet-like clusters [12], hepatocyte-like cells [13,14] and a number of cardiovascular cells (arterial endothelium, venous endothelium, lymphatic endothelium, cardiomyocytes), but not kidney [15,16].

This chapter first summarizes the mechanisms of kidney development and the research on the directed differentiation of ESCs into renal lineages based on the knowledge of kidney development. In vitro generation of kidney using the undifferentiated cell mass in amphibian eggs, similar to mammalian pluripotent stem cells in that the cell mass can differentiate into various organs in vitro, is also described as a reference to kidney regeneration in mammals. Recent advances in the iPS cell research and technology are then reviewed, and finally the future direction of iPS cells in the field of regenerative nephrology is described.

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Induced Pluripotent Stem Cell - an overview ...

IPS Cell Therapy Comments Off on Induced Pluripotent Stem Cell – an overview … | November 28th, 2020

Stem cell-derived cells are ready-made human induced pluripotent stem cells (iPS) and iPS-derived cell lines that are extracted ethically and have been characterized as per highest industry standards. Stem cell-derived cells iPS cells are derived from the skin fibroblasts from variety of healthy human donors of varying age and gender. These stem cell-derived cells are then commercialized for use with the consent obtained from cell donors. These stem cell-derived cells are then developed using a complete culture system that is an easy-to-use system used for defined iPS-derived cell expansion. Majority of the key players in stem cell-derived cells market are focused on generating high-end quality cardiomyocytes as well as hepatocytes that enables end use facilities to easily obtain ready-made iPSC-derived cells. As the stem cell-derived cells market registers a robust growth due to rapid adoption in stem cellderived cells therapy products, there is a relative need for regulatory guidelines that need to be maintained to assist designing of scientifically comprehensive preclinical studies. The stem cell-derived cells obtained from human induced pluripotent stem cells (iPS) are initially dissociated into a single-cell suspension and later frozen in vials. The commercially available stem cell-derived cell kits contain a vial of stem cell-derived cells, a bottle of thawing base and culture base.

The increasing approval for new stem cell-derived cells by the FDA across the globe is projected to propel stem cell-derived cells market revenue growth over the forecast years. With low entry barriers, a rise in number of companies has been registered that specializes in offering high end quality human tissue for research purpose to obtain human induced pluripotent stem cells (iPS) derived cells. The increase in product commercialization activities for stem cell-derived cells by leading manufacturers such as Takara Bio Inc. With the increasing rise in development of stem cell based therapies, the number of stem cell-derived cells under development or due for FDA approval is anticipated to increase, thereby estimating to be the most prominent factor driving the growth of stem cell-derived cells market. However, high costs associated with the development of stem cell-derived cells using complete culture systems is restraining the revenue growth in stem cell-derived cells market.

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The global Stem cell-derived cells market is segmented on basis of product type, material type, application type, end user and geographic region:

Segmentation by Product Type

Segmentation by End User

The stem cell-derived cells market is categorized based on product type and end user. Based on product type, the stem cell-derived cells are classified into two major types stem cell-derived cell kits and accessories. Among these stem cell-derived cell kits, stem cell-derived hepatocytes kits are the most preferred stem cell-derived cells product type. On the basis of product type, stem cell-derived cardiomyocytes kits segment is projected to expand its growth at a significant CAGR over the forecast years on the account of more demand from the end use segments. However, the stem cell-derived definitive endoderm cell kits segment is projected to remain the second most lucrative revenue share segment in stem cell-derived cells market. Biotechnology and pharmaceutical companies followed by research and academic institutions is expected to register substantial revenue growth rate during the forecast period.

To receive extensive list of important regions, Request Methodology here @

https://www.persistencemarketresearch.com/methodology/28780

North America and Europe cumulatively are projected to remain most lucrative regions and register significant market revenue share in global stem cell-derived cells market due to the increased patient pool in the regions with increasing adoption for stem cell based therapies. The launch of new stem cell-derived cells kits and accessories on FDA approval for the U.S. market allows North America to capture significant revenue share in stem cell-derived cells market. Asian countries due to strong funding in research and development are entirely focused on production of stem cell-derived cells thereby aiding South Asian and East Asian countries to grow at a robust CAGR over the forecast period.

Some of the major key manufacturers involved in global stem cell-derived cells market are Takara Bio Inc., Viacyte, Inc. and others.

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To support companies in overcoming complex business challenges, we follow a multi-disciplinary approach. At PMR, we unite various data streams from multi-dimensional sources. By deploying real-time data collection, big data, and customer experience analytics, we deliver business intelligence for organizations of all sizes.

Our client success stories feature a range of clients from Fortune 500 companies to fast-growing startups. PMRs collaborative environment is committed to building industry-specific solutions by transforming data from multiple streams into a strategic asset.

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The Stem Cell-Derived Cells market to Scale new heights in the next decade - Khabar South Asia

IPS Cell Therapy Comments Off on The Stem Cell-Derived Cells market to Scale new heights in the next decade – Khabar South Asia | November 28th, 2020

Stem Cells Market Overview:

Reports and Data has recently published a new research study titled Global Stem Cells Market that offers accurate insights for the Stem Cells market formulated with extensive research. The report explores the shifting focus observed in the market to offer the readers data and enable them to capitalize on market development. The report explores the essential industry data and generates a comprehensive document covering key geographies, technology developments, product types, applications, business verticals, sales network and distribution channels, and other key segments.

The report is further furnished with the latest market changes and trends owing to the global COVID-19 crisis. The report explores the impact of the crisis on the market and offers a comprehensive overview of the segments and sub-segments affected by the crisis. The study covers the present and future impact of the pandemic on the overall growth of the industry.

Get a sample of the report @ https://www.reportsanddata.com/sample-enquiry-form/2981

Competitive Landscape:

The global Stem Cells market is consolidated owing to the existence of domestic and international manufacturers and vendors in the market. The prominent players of the key geographies are undertaking several business initiatives to gain a robust footing in the industry. These strategies include mergers and acquisitions, product launches, joint ventures, collaborations, partnerships, agreements, and government deals. These strategies assist them in carrying out product developments and technological advancements.

The report covers extensive analysis of the key market players in the market, along with their business overview, expansion plans, and strategies. The key players studied in the report include:

Celgene Corporation, ReNeuron Group plc, Virgin Health Bank, Biovault Family, Mesoblast Ltd., Caladrius, Opexa Therapeutics, Inc., Precious Cells International Ltd., Pluristem, and Neuralstem, Inc., among others.

An extensive analysis of the market dynamics, including a study of drivers, constraints, opportunities, risks, limitations, and threats have been studied in the report. The report offers region-centric data and analysis of the micro and macro-economic factors affecting the growth of the overall Stem Cells market. The report offers a comprehensive assessment of the growth prospects, market trends, revenue generation, product launches, and other strategic business initiatives to assist the readers in formulating smart investment and business strategies.

To read more about the report, visit @ https://www.reportsanddata.com/report-detail/stem-cells-market

Product Outlook (Revenue, USD Billion; 2017-2027)

Technology Outlook (Revenue, USD Billion; 2017-2027)

Therapy Outlook (Revenue, USD Billion; 2017-2027)

Application Outlook (Revenue, USD Billion; 2017-2027)

Request a discount on the report @ https://www.reportsanddata.com/discount-enquiry-form/2981

Key Coverage in the Stem Cells Market Report:

Thank you for reading our report. Please get in touch with us if you have any queries regarding the report or its customization. Our team will make sure the report is tailored to meet your requirements.

Take a look at other reports from Reports and Data on PR Newswire:

Hydroxycitronellal Market: Hydroxycitronellal Market To Reach USD 192.7 Million By 2027

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About Us:

Our in-house experts assist our clients with advice based on their proficiency in the market that helps them in creating a compendious database for the clients. Our team offers expert insights to clients to guide them through their business ventures. We put in rigorous efforts to keep our clientele satisfied and focus on fulfilling their demands to make sure that the end-product is what they desire. We excel in diverse fields of the market and with our services extending to competitive analysis, research and development analysis, and demand estimation among others, we can help you invest your funds in the most beneficial areas for research and development. You can rely on us to provide every significant detail you might need in your efforts to make your business flourish.

Contact Us:

John Watson

Head of Business Development

Reports and Data|Web:www.reportsanddata.com

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Stem Cells Market 2020: Rising with Immense Development Trends across the Globe by 2027 - The Market Feed

IPS Cell Therapy Comments Off on Stem Cells Market 2020: Rising with Immense Development Trends across the Globe by 2027 – The Market Feed | November 25th, 2020

Stem cell-derived cells are ready-made human induced pluripotent stem cells (iPS) and iPS-derived cell lines that are extracted ethically and have been characterized as per highest industry standards. Stem cell-derived cells iPS cells are derived from the skin fibroblasts from variety of healthy human donors of varying age and gender. These stem cell-derived cells are then commercialized for use with the consent obtained from cell donors. These stem cell-derived cells are then developed using a complete culture system that is an easy-to-use system used for defined iPS-derived cell expansion. Majority of the key players in stem cell-derived cells market are focused on generating high-end quality cardiomyocytes as well as hepatocytes that enables end use facilities to easily obtain ready-made iPSC-derived cells. As the stem cell-derived cells market registers a robust growth due to rapid adoption in stem cellderived cells therapy products, there is a relative need for regulatory guidelines that need to be maintained to assist designing of scientifically comprehensive preclinical studies. The stem cell-derived cells obtained from human induced pluripotent stem cells (iPS) are initially dissociated into a single-cell suspension and later frozen in vials. The commercially available stem cell-derived cell kits contain a vial of stem cell-derived cells, a bottle of thawing base and culture base.

The increasing approval for new stem cell-derived cells by the FDA across the globe is projected to propel stem cell-derived cells market revenue growth over the forecast years. With low entry barriers, a rise in number of companies has been registered that specializes in offering high end quality human tissue for research purpose to obtain human induced pluripotent stem cells (iPS) derived cells. The increase in product commercialization activities for stem cell-derived cells by leading manufacturers such as Takara Bio Inc. With the increasing rise in development of stem cell based therapies, the number of stem cell-derived cells under development or due for FDA approval is anticipated to increase, thereby estimating to be the most prominent factor driving the growth of stem cell-derived cells market. However, high costs associated with the development of stem cell-derived cells using complete culture systems is restraining the revenue growth in stem cell-derived cells market.

To remain ahead of your competitors, request for a sample[emailprotected]

https://www.persistencemarketresearch.com/samples/28780

The global Stem cell-derived cells market is segmented on basis of product type, material type, application type, end user and geographic region:

Segmentation by Product Type

Segmentation by End User

The stem cell-derived cells market is categorized based on product type and end user. Based on product type, the stem cell-derived cells are classified into two major types stem cell-derived cell kits and accessories. Among these stem cell-derived cell kits, stem cell-derived hepatocytes kits are the most preferred stem cell-derived cells product type. On the basis of product type, stem cell-derived cardiomyocytes kits segment is projected to expand its growth at a significant CAGR over the forecast years on the account of more demand from the end use segments. However, the stem cell-derived definitive endoderm cell kits segment is projected to remain the second most lucrative revenue share segment in stem cell-derived cells market. Biotechnology and pharmaceutical companies followed by research and academic institutions is expected to register substantial revenue growth rate during the forecast period.

To receive extensive list of important regions, Request Methodology here @

https://www.persistencemarketresearch.com/methodology/28780

North America and Europe cumulatively are projected to remain most lucrative regions and register significant market revenue share in global stem cell-derived cells market due to the increased patient pool in the regions with increasing adoption for stem cell based therapies. The launch of new stem cell-derived cells kits and accessories on FDA approval for the U.S. market allows North America to capture significant revenue share in stem cell-derived cells market. Asian countries due to strong funding in research and development are entirely focused on production of stem cell-derived cells thereby aiding South Asian and East Asian countries to grow at a robust CAGR over the forecast period.

Some of the major key manufacturers involved in global stem cell-derived cells market are Takara Bio Inc., Viacyte, Inc. and others.

You Can Request for TOC[emailprotected]

https://www.persistencemarketresearch.com/toc/28780

Explore Extensive Coverage of PMR`s

Life Sciences & Transformational HealthLandscape

About us:

Persistence Market Research (PMR) is a third-platform research firm. Our research model is a unique collaboration of data analytics andmarket research methodologyto help businesses achieve optimal performance.

To support companies in overcoming complex business challenges, we follow a multi-disciplinary approach. At PMR, we unite various data streams from multi-dimensional sources. By deploying real-time data collection, big data, and customer experience analytics, we deliver business intelligence for organizations of all sizes.

Our client success stories feature a range of clients from Fortune 500 companies to fast-growing startups. PMRs collaborative environment is committed to building industry-specific solutions by transforming data from multiple streams into a strategic asset.

Contact us:

Naved BegPersistence Market ResearchAddress 305 Broadway, 7th Floor, New York City,NY 10007 United StatesU.S. Ph. +1-646-568-7751USA-Canada Toll-free +1 800-961-0353Sales[emailprotected]Websitehttps://www.persistencemarketresearch.com

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The Stem Cell-Derived Cells Market to witness explicit growth from 2019 and 2029 - The Haitian-Caribbean News Network

IPS Cell Therapy Comments Off on The Stem Cell-Derived Cells Market to witness explicit growth from 2019 and 2029 – The Haitian-Caribbean News Network | November 23rd, 2020

Stem Cells Market Overview:

Reports and Data has recently published a new research study titled Global Stem Cells Market that offers accurate insights for the Stem Cells market formulated with extensive research. The report explores the shifting focus observed in the market to offer the readers data and enable them to capitalize on market development. The report explores the essential industry data and generates a comprehensive document covering key geographies, technology developments, product types, applications, business verticals, sales network and distribution channels, and other key segments.

The global Stem Cells market is forecasted to grow at a rate of 8.4% from USD 9.35 billion in 2019 to USD 17.78 billion in 2027.

The report is further furnished with the latest market changes and trends owing to the global COVID-19 crisis. The report explores the impact of the crisis on the market and offers a comprehensive overview of the segments and sub-segments affected by the crisis. The study covers the present and future impact of the pandemic on the overall growth of the industry.

Get a sample of the report @ https://www.reportsanddata.com/sample-enquiry-form/2981

Competitive Landscape:

The global Stem Cells market is consolidated owing to the existence of domestic and international manufacturers and vendors in the market. The prominent players of the key geographies are undertaking several business initiatives to gain a robust footing in the industry. These strategies include mergers and acquisitions, product launches, joint ventures, collaborations, partnerships, agreements, and government deals. These strategies assist them in carrying out product developments and technological advancements.

The report covers extensive analysis of the key market players in the market, along with their business overview, expansion plans, and strategies. The key players studied in the report include:

Thermo Fisher Scientific, Agilent Technologies, Illumina, Inc., Qiagen, Oxford Nanopore Technologies, Eurofins Scientific, F. Hoffmann-La Roche, Danaher Corporation, Bio-Rad Laboratories, and GE Healthcare.

An extensive analysis of the market dynamics, including a study of drivers, constraints, opportunities, risks, limitations, and threats have been studied in the report. The report offers region-centric data and analysis of the micro and macro-economic factors affecting the growth of the overall Stem Cells market. The report offers a comprehensive assessment of the growth prospects, market trends, revenue generation, product launches, and other strategic business initiatives to assist the readers in formulating smart investment and business strategies.

To read more about the report, visit @ https://www.reportsanddata.com/report-detail/stem-cells-market

Product Outlook (Revenue, USD Billion; 2017-2027)

Technology Outlook (Revenue, USD Billion; 2017-2027)

Therapy Outlook (Revenue, USD Billion; 2017-2027)

Application Outlook (Revenue, USD Billion; 2017-2027)

Request a discount on the report @ https://www.reportsanddata.com/discount-enquiry-form/2981

Key Coverage in the Stem Cells Market Report:

Thank you for reading our report. Please get in touch with us if you have any queries regarding the report or its customization. Our team will make sure the report is tailored to meet your requirements.

Take a look at other reports from Reports and Data on PR Newswire:

Hydroxycitronellal Market: Hydroxycitronellal Market To Reach USD 192.7 Million By 2027

Sterile Filtration Market: Sterile Filtration Market To Reach USD 8.48 Billion By 2027 | CAGR: 7.7%

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UV-C Robot Market: UV-C Robot Market to Reach USD 1.46 Billion by 2027

About Us:

Our in-house experts assist our clients with advice based on their proficiency in the market that helps them in creating a compendious database for the clients. Our team offers expert insights to clients to guide them through their business ventures. We put in rigorous efforts to keep our clientele satisfied and focus on fulfilling their demands to make sure that the end-product is what they desire. We excel in diverse fields of the market and with our services extending to competitive analysis, research and development analysis, and demand estimation among others, we can help you invest your funds in the most beneficial areas for research and development. You can rely on us to provide every significant detail you might need in your efforts to make your business flourish.

Contact Us:

John Watson

Head of Business Development

Reports and Data|Web:www.reportsanddata.com

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The rest is here:
Stem Cells Market Research Provides an In-Depth Analysis on the Future Growth Prospects and Industry Trends Adopted by the Competitors | (2020-2027),...

IPS Cell Therapy Comments Off on Stem Cells Market Research Provides an In-Depth Analysis on the Future Growth Prospects and Industry Trends Adopted by the Competitors | (2020-2027),… | November 23rd, 2020

Stem cell-derived cells are ready-made human induced pluripotent stem cells (iPS) and iPS-derived cell lines that are extracted ethically and have been characterized as per highest industry standards. Stem cell-derived cells iPS cells are derived from the skin fibroblasts from variety of healthy human donors of varying age and gender. These stem cell-derived cells are then commercialized for use with the consent obtained from cell donors. These stem cell-derived cells are then developed using a complete culture system that is an easy-to-use system used for defined iPS-derived cell expansion. Majority of the key players in stem cell-derived cells market are focused on generating high-end quality cardiomyocytes as well as hepatocytes that enables end use facilities to easily obtain ready-made iPSC-derived cells. As the stem cell-derived cells market registers a robust growth due to rapid adoption in stem cellderived cells therapy products, there is a relative need for regulatory guidelines that need to be maintained to assist designing of scientifically comprehensive preclinical studies. The stem cell-derived cells obtained from human induced pluripotent stem cells (iPS) are initially dissociated into a single-cell suspension and later frozen in vials. The commercially available stem cell-derived cell kits contain a vial of stem cell-derived cells, a bottle of thawing base and culture base.

The increasing approval for new stem cell-derived cells by the FDA across the globe is projected to propel stem cell-derived cells market revenue growth over the forecast years. With low entry barriers, a rise in number of companies has been registered that specializes in offering high end quality human tissue for research purpose to obtain human induced pluripotent stem cells (iPS) derived cells. The increase in product commercialization activities for stem cell-derived cells by leading manufacturers such as Takara Bio Inc. With the increasing rise in development of stem cell based therapies, the number of stem cell-derived cells under development or due for FDA approval is anticipated to increase, thereby estimating to be the most prominent factor driving the growth of stem cell-derived cells market. However, high costs associated with the development of stem cell-derived cells using complete culture systems is restraining the revenue growth in stem cell-derived cells market.

To remain ahead of your competitors, request for a sample[emailprotected]

https://www.persistencemarketresearch.com/samples/28780

The global Stem cell-derived cells market is segmented on basis of product type, material type, application type, end user and geographic region:

Segmentation by Product Type

Segmentation by End User

The stem cell-derived cells market is categorized based on product type and end user. Based on product type, the stem cell-derived cells are classified into two major types stem cell-derived cell kits and accessories. Among these stem cell-derived cell kits, stem cell-derived hepatocytes kits are the most preferred stem cell-derived cells product type. On the basis of product type, stem cell-derived cardiomyocytes kits segment is projected to expand its growth at a significant CAGR over the forecast years on the account of more demand from the end use segments. However, the stem cell-derived definitive endoderm cell kits segment is projected to remain the second most lucrative revenue share segment in stem cell-derived cells market. Biotechnology and pharmaceutical companies followed by research and academic institutions is expected to register substantial revenue growth rate during the forecast period.

To receive extensive list of important regions, Request Methodology here @

https://www.persistencemarketresearch.com/methodology/28780

North America and Europe cumulatively are projected to remain most lucrative regions and register significant market revenue share in global stem cell-derived cells market due to the increased patient pool in the regions with increasing adoption for stem cell based therapies. The launch of new stem cell-derived cells kits and accessories on FDA approval for the U.S. market allows North America to capture significant revenue share in stem cell-derived cells market. Asian countries due to strong funding in research and development are entirely focused on production of stem cell-derived cells thereby aiding South Asian and East Asian countries to grow at a robust CAGR over the forecast period.

Some of the major key manufacturers involved in global stem cell-derived cells market are Takara Bio Inc., Viacyte, Inc. and others.

You Can Request for TOC[emailprotected]

https://www.persistencemarketresearch.com/toc/28780

Explore Extensive Coverage of PMR`s

Life Sciences & Transformational HealthaLandscape

About us:

Persistence Market Research (PMR) is a third-platform research firm. Our research model is a unique collaboration of data analytics andmarket research methodologyto help businesses achieve optimal performance.

To support companies in overcoming complex business challenges, we follow a multi-disciplinary approach. At PMR, we unite various data streams from multi-dimensional sources. By deploying real-time data collection, big data, and customer experience analytics, we deliver business intelligence for organizations of all sizes.

Our client success stories feature a range of clients from Fortune 500 companies to fast-growing startups. PMRs collaborative environment is committed to building industry-specific solutions by transforming data from multiple streams into a strategic asset.

Contact us:

Naved BegPersistence Market ResearchAddress 305 Broadway, 7th Floor, New York City,NY 10007 United StatesU.S. Ph. +1-646-568-7751USA-Canada Toll-free +1 800-961-0353Sales[emailprotected]Websitehttps://www.persistencemarketresearch.com

Read more:
The Stem Cell-Derived Cells market to go the astute way from 2019 to 2029 - TechnoWeekly

IPS Cell Therapy Comments Off on The Stem Cell-Derived Cells market to go the astute way from 2019 to 2029 – TechnoWeekly | November 3rd, 2020

The latest market report published by Reports and Data, titled Global Stem Cells Market, presents an accurate analysis of the estimated market size, share, revenue, and sales & distribution networks of the global Stem Cells market over the forecast period. The report offers an exhaustive overview of the market, along with a precise summary of the markets leading regions. Our team of analysts has studied the existing competitive landscape of the market inside out, focusing on the leading companies and their business expansion strategies. The report ends with conclusive data offering useful insights into the market growth on both regional and global levels.

The report covers extensive analysis of the key market players in the market, along with their business overview, expansion plans, and strategies. The key players studied in the report include:

Thermo Fisher Scientific, Agilent Technologies, Illumina, Inc., Qiagen, Oxford Nanopore Technologies, Eurofins Scientific, F. Hoffmann-La Roche, Danaher Corporation, Bio-Rad Laboratories, and GE Healthcare

Get a sample of the report @ https://www.reportsanddata.com/sample-enquiry-form/2981

The report draws the focus of the reader on the grave impact of the ongoing COVID-19 pandemic on the Stem Cells industry and its vital segments and sub-segments. It elaborates on the adverse effects of the pandemic on the global economic scenario, as well as this particular business sphere. The report takes into account the key influencing factors influencing market performance in the present COVID-19 times. The market has been substantially affected by the pandemic, and significant changes have been observed in the market dynamics and demand trends. The report examines the major financial difficulties brought about by the pandemic and offers a future COVID-19 impact assessment.

The market intelligence study takes the reader through the key parameters of the Stem Cells market, including the strengths and weaknesses of the leading players, using analytical tools like the SWOT analysis and Porters Five Forces analysis. The report includes broad market segmentation based on the different product types, a wide application spectrum, the key regions, and the existing competition among players.

Product Outlook (Revenue, USD Billion; 2017-2027)

Technology Outlook (Revenue, USD Billion; 2017-2027)

Therapy Outlook (Revenue, USD Billion; 2017-2027)

Application Outlook (Revenue, USD Billion; 2017-2027)

Request a discount on the report @ https://www.reportsanddata.com/discount-enquiry-form/2981

The investigative study further assesses the market on the basis of market reach and consumer base in the key geographical segments. Alongside reviewing the sales network, distribution channels, pricing analysis, profit margins, cost and demand volatility, import/export dynamics, gross revenue, and various other aspects of the market, the report studies several factors affecting market growth over the forecast period, such as drivers, restraints, limitations, growth prospects, and numerous macro- and micro-economic indicators.

Key Geographies Encompassed in the Report:

Key questions addressed in the report:

To read more about the report, visit @ https://www.reportsanddata.com/report-detail/stem-cells-market

Thank you for reading our report. For further queries regarding the report, please get in touch with us. Our team will ensure your report is customized as per your requirements.

About Us:

Our in-house experts assist our clients with advice based on their proficiency in the market that helps them in creating a compendious database for the clients. Our team offers expert insights to clients to guide them through their business ventures. We put in rigorous efforts to keep our clientele satisfied and focus on fulfilling their demands to make sure that the end-product is what they desire. We excel in diverse fields of the market and with our services extending to competitive analysis, research and development analysis, and demand estimation among others, we can help you invest your funds in the most beneficial areas for research and development. You can rely on us to provide every significant detail you might need in your efforts to make your business flourish.

Contact Us:

John Watson

Head of Business Development

Reports and Data|Web:www.reportsanddata.com

Direct Line:+1-212-710-1370

E-mail:[emailprotected]

Link:
Global Stem Cells Market 2020 Industry Demand, Share, Global Trend, Top Key Players Update, Business Statistics And Research Methodology By Forecast...

IPS Cell Therapy Comments Off on Global Stem Cells Market 2020 Industry Demand, Share, Global Trend, Top Key Players Update, Business Statistics And Research Methodology By Forecast… | November 3rd, 2020