Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and …

Background

Since they were first derived more than three decades ago, embryonic stem cells have been proposed as a source of replacement cells in regenerative medicine, but their plasticity and unlimited capacity for self-renewal raises concerns about their safety, including tumour formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types. We report the medium-term to long-term safety of cells derived from human embryonic stem cells (hESC) transplanted into patients.

There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. 13 (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 1625 points 312 months after transplantation in patients with atrophic age-related macular degeneration and 820 points in patients with Stargardt's macular dystrophy.

The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that hESC-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement.

Advanced Cell Technology.

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Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and ...

Mount Sinai Researchers Awarded $1 Million Grant to Find New Stem Cell Therapies for Vision Recovery

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Newswise NEW YORK November 20, 2014 The National Eye Institute (NEI), a division of the National Institutes of Health, has awarded researchers at the Icahn School of Medicine at Mount Sinai a five-year grant that will support an effort to re-create a patients ocular stem cells and restore vision in those blinded by corneal disease.

About six million people worldwide have been blinded by burns, trauma, infection, genetic diseases, and chronic inflammation that result in corneal stem cell death and corneal scarring. There are currently no treatments for related vision loss that are effective over the long term. Corneal stem cell transplantation is an option in the short term, but availability of donor corneas is limited, and patients must take medications that suppress their immune systems for the rest of their lives to prevent rejection of the transplanted tissue.

A newer proposed treatment option is the replacement of corneal stem cells to restore vision. The grant from the NEI will fund Mount Sinai research to re-create a patients own stem cells and restore vision in those blinded by corneal disease. Technological advances in recent years have enabled researchers to take mature cells, in this case eyelid or oral skin cells, and coax them backward along the development pathways to become stem cells again. These eye-specific stem cells would then be redirected down pathways that become needed replacements for damaged cells in the cornea, in theory restoring vision.

Our findings will allow the creation of transplantable eye tissue that can restore the ocular surface, said Albert Y. Wu, MD, PhD, Assistant Professor, Department of Ophthalmology at the Icahn School of Medicine at Mount Sinai and principle investigator for the grant-funded effort. In the future, we will be able to re-create a patients own corneal stem cells to restore vision after being blind, added Dr. Wu, also Director of the Ophthalmic Plastic and Reconstructive Surgery, Stem Cell and Regenerative Medicine Laboratory in the Department of Ophthalmology and a member of the Black Family Stem Cell Institute at Icahn School of Medicine. Since the stem cells are their own, patients will not require immunosuppressive drugs, which would greatly improve their quality of life.

Specifically, the grant will support efforts to discover new stem cell therapies for ocular surface disease and make regenerative medicine a reality for people who have lost their vision. The research team will investigate the most viable stem cell sources, seek to create ocular stem cells from eyelid or oral skin cells, explore the molecular pathways involved in ocular and orbital development, and develop cutting-edge biomaterials to engraft a patients own stem cells and restore vision.

Other investigators from Mount Sinai include Ihor Lemischka, PhD, Director, Black Family Stem Cell Institute and J. Mario Wolosin, PhD, Professor of Ophthalmology. The research is supported by NEI grant EY023997.

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Mount Sinai Researchers Awarded $1 Million Grant to Find New Stem Cell Therapies for Vision Recovery

Humans' big brains might be due in part to newly identified protein

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12-Nov-2014

Contact: Scott Maier scott.maier@ucsf.edu 415-502-6397 University of California - San Francisco @ucsf

A protein that may partly explain why human brains are larger than those of other animals has been identified by scientists from two stem-cell labs at UC San Francisco, in research published in the November 13, 2014 issue of Nature.

Key experiments by the UCSF researchers revealed that the protein, called PDGFD, is made in growing brains of humans, but not in mice, and appears necessary for normal proliferation of human brain stem cells growing in a lab dish.

The scientists made their discovery as part of research in which they identified genes that are activated to make specific proteins in crucial stem cells in the brain known as radial glial cells. The discovery stems from a collaboration between the laboratories of leading radial glial cell scientist Arnold Kriegstein MD, PhD, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, and Michael Oldham, PhD, who recently made a rapid career leap from graduate student to principal investigator and Sandler Fellow at UCSF.

Radial glial cells make the neurons in the growing brain, including the neurons in the cerebral cortex, the seat of higher brain functions. The cerebral cortex varies in size 10,000-fold among mammals. Changes in the timing, location and degree of cell division and nerve cell generation by radial glial cells can dramatically alter the shape and function of the cortex.

The UCSF team discovered that PDGFD is secreted by human radial glial cells and acts on radial glial cells as well as other progenitor cells in the developing brain.

"To the best of our knowledge this is the first example of any signaling pathway affecting the proliferation of radial glial cells whose activity has changed during mammalian evolution," Oldham said. "We think that the expression of PDGFD in this signaling pathway is likely to be part of the reason the human brain is so much bigger that the mouse brain."

Although the UCSF research team found that the majority of genes that are active in radial glial cells are the same in humans and mice, they identified 18 genes that are active in human but not mouse radial glial cells during development of the cerebral cortex.

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Humans' big brains might be due in part to newly identified protein

Toughest for Tamil Nadu patients to get donor stem cells

CHENNAI: It is harder for natives of Tamil Nadu to find a matching donor for a stem cell transplant compared to other states in the country. The suspected villain: Their genes.

A study published recently in British medical journal 'The Lancet' found that the likelihood of finding a matching stem cell donor for patients with blood-related problems in Tamil Nadu is 44.2% provided the registry had 10 lakh donors. The situation is the opposite in Haryana, with people in that state having the best chances (81.2%) of finding a donor.

Experts say consanguineous marriages are to blame. Consanguineous marriages increase the chances of patients finding a match within their small community but limit the possibility of finding one from a general donor pool.

"Unlike in other countries, stem cell variation in India is complex and dependent on ethnic variation," said Dr Dolly Daniel, professor of the department of transfusion medicine at Christian Medical College, Vellore, who was party of the study team. "Our aim was to find the size and genetic composition of each region and its impact on the proportion of patients who will be able to ?nd a suitable match."

She said Tamil Nadu could be at the tail-end of the list of states they surveyed because of inbreeding and a limited number of donors.

Stem cells are used to regenerate and repair diseased or damaged tissues. Adult stem cells are drawn from bone marrow, blood and the umbilical cord and are used to treat blood-related ailments like leukemia, thalassemia and as well as immunodeficiency.

The possibility of finding a matching stem cell donor within the family is around 30%.

"Finding a matching stem cell donor for the remaining 70% is a complex process. Most seek a graft from registries of unrelated adult donors or banked umbilical cord blood units," said Dr P Srinivasan, co-founder and chairman of Jeevan Stem Cell Bank.

Although the India stem cell industry is estimated to touch $540 million (Rs 3,250 crore) by 2015, the study noted that in terms of the number of donors, India has lagged in meeting demand. The study surveyed 10 adult donor and umbilical cord bank registries and clinical transplant centres in India and studied stem cells of 26 239 individuals.

The possibility of finding a perfect match within India is an average of 14.4% for a registry size of 25,000 and touches 60.6% for a size of 10 lakh. Registries in the country currently have around 1 lakh donors. The study said only when Indian registries have more than 2 lakh donors would patients have a good chance of finding the right match.

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Toughest for Tamil Nadu patients to get donor stem cells

BioEden the specialist tooth stem cell bank announce record sales up 45%

(PRWEB UK) 9 November 2014

Every day stem cell treatments are in the news, often bringing the last hope for many patients with serious conditions that have defied traditional medicine.

BioEden's Group CEO Tony Veverka says, 'the increase in popularity in banking a persons own cells is as a result of two main things; 1. The likelihood of needing stem cell therapy is high, and 2. You need a stem cell match - your own cells are the perfect match'.

BioEden's tooth stem cell banking service is the only way you can access your own cells without the need for medical intervention. More and more parents are choosing to bank their children's stem cells as the baby tooth is shed naturally. However, stem cells can be banked from a healthy adult molar, that perhaps is being removed for orthodontic reasons.

Obtaining stem cells from other sources such as bone marrow is not only invasive but costly. Taking the decision to bank ones own cells is a sensible consideration, and costs from just 295.

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BioEden the specialist tooth stem cell bank announce record sales up 45%

Before there will be blood: Pro-inflammatory signaling plays surprising role in creation of hematopoietic stem cells

8 hours ago In this multiple confocal analysis of transverse sections from transgenic zebrafish embryos, vasculature is labeled by red fluorescence, NF-kB protein complex that regulates inflammation by green fluorescence and nuclei by blue fluorescence. The arrowhead indicates a potential hematopoietic stem cell emerging in the dorsal aorta with high expression of NF-kB. The image at bottom right combines all channels. Credit: UC San Diego School of Medicine

Hematopoietic stem cells (HSCs) give rise to all blood and immune cells throughout the life of vertebrate organisms, from zebrafish to humans. But details of their genesis remain elusive, hindering efforts to develop induced pluripotent stem cell (iPSC) replacements that might address a host of blood disorders.

In a paper published Nov. 20 in the journal Cell, researchers at the University of California, San Diego School of Medicine describe the surprising and crucial involvement of a pro-inflammatory signaling protein in the creation of HSCs during embryonic development, a finding that could help scientists to finally reproduce HSCs for therapeutic use.

"The recent breakthrough of induced pluripotency has made the concept of patient-specific regenerative medicine a reality," said principal investigator David Traver, PhD, professor in the Department of Cellular and Molecular Medicine. "The development of some mature cell lineages from iPSCs, such as cardiac and neural, has been reasonably straightforward, but not with HSCs. This is likely due, at least in part, to not fully understanding all of the factors used by the embryo to generate HSCs. We believe the discovery that pro-inflammatory cues are important in vivo will help us recapitulate instruction of HSC fate in vitro from iPSCs."

Traver and colleagues specifically looked at the role of a cytokine (a type of cell signaling protein) called tumor necrosis factor alpha or TNF, which plays a pivotal role in regulating systemic inflammation and immunity. The work extended previous research by Spanish biologist Victoriano Mulero, who had reported that TNF was important in the function of the embryonic vascular system and that in animal models where TNF function was absent, blood defects resulted.

The Cell paper's first author Raquel Espin-Palazon, a postdoctoral researcher in Traver's lab and a former colleague of Mulero's, determined that TNF was required for the emergence of hematopoietic stem cells during embryogenesis in zebrafish a common animal model.

Traver said the finding was completely unexpected because HSCs emerge relatively early in embryonic formation when the developing organism is considered to be largely sterile and devoid of infection.

"Thus, there was no expectation that pro-inflammatory signaling would be active at this time or in the blood-forming regions," Traver said. "Equally surprising, we found that a population of embryonic myeloid cells, which are transient cells produced before HSCs arise, are the producers of the TNF needed to establish HSC fate. So it turns out that a small subset of myeloid cells that persist for only a few days in development are necessary to help generate the lineal precursors of the entire adult blood-forming system."

The newly discovered role of TNF in HSC development mirrors a parallel discovery regarding interferon gamma (INFg), another cytokine and major mediator of pro-inflammatory signaling, highlighting multiple inputs for inflammatory signaling in HSC emergence. Traver said the crucial roles of TNF and INFg in HSC emergence are likely similar in humans because of the highly conserved nature of HSC development across vertebrate evolution.

Explore further: New blood: Tracing the beginnings of hematopoietic stem cells

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Before there will be blood: Pro-inflammatory signaling plays surprising role in creation of hematopoietic stem cells

Before There Will Be Blood

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Newswise Hematopoietic stem cells (HSCs) give rise to all blood and immune cells throughout the life of vertebrate organisms, from zebrafish to humans. But details of their genesis remain elusive, hindering efforts to develop induced pluripotent stem cell (iPSC) replacements that might address a host of blood disorders.

In a paper published Nov. 20 in the journal Cell, researchers at the University of California, San Diego School of Medicine describe the surprising and crucial involvement of a pro-inflammatory signaling protein in the creation of HSCs during embryonic development, a finding that could help scientists to finally reproduce HSCs for therapeutic use.

The recent breakthrough of induced pluripotency has made the concept of patient-specific regenerative medicine a reality, said principal investigator David Traver, PhD, professor in the Department of Cellular and Molecular Medicine. The development of some mature cell lineages from iPSCs, such as cardiac and neural, has been reasonably straightforward, but not with HSCs. This is likely due, at least in part, to not fully understanding all of the factors used by the embryo to generate HSCs. We believe the discovery that pro-inflammatory cues are important in vivo will help us recapitulate instruction of HSC fate in vitro from iPSCs.

Traver and colleagues specifically looked at the role of a cytokine (a type of cell signaling protein) called tumor necrosis factor alpha or TNFa, which plays a pivotal role in regulating systemic inflammation and immunity. The work extended previous research by Spanish biologist Victoriano Mulero, who had reported that TNFa was important in the function of the embryonic vascular system and that in animal models where TNF function was absent, blood defects resulted.

The Cell papers first author Raquel Espin-Palazon, a postdoctoral researcher in Travers lab and a former colleague of Muleros, determined that TNFa was required for the emergence of hematopoietic stem cells during embryogenesis in zebrafish a common animal model.

Traver said the finding was completely unexpected because HSCs emerge relatively early in embryonic formation when the developing organism is considered to be largely sterile and devoid of infection.

Thus, there was no expectation that pro-inflammatory signaling would be active at this time or in the blood-forming regions, Traver said. Equally surprising, we found that a population of embryonic myeloid cells, which are transient cells produced before HSCs arise, are the producers of the TNFa needed to establish HSC fate. So it turns out that a small subset of myeloid cells that persist for only a few days in development are necessary to help generate the lineal precursors of the entire adult blood-forming system.

The newly discovered role of TNFa in HSC development mirrors a parallel discovery regarding interferon gamma (INFg), another cytokine and major mediator of pro-inflammatory signaling, highlighting multiple inputs for inflammatory signaling in HSC emergence. Traver said the crucial roles of TNFa and INFg in HSC emergence are likely similar in humans because of the highly conserved nature of HSC development across vertebrate evolution.

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Before There Will Be Blood

Lab-grown stem cell trial gets green light

Irelands first human stem cell trial using lab-grown cells is due to get underway in Galway in the new year following approval from the medicines watchdog.

The trial will involve extracting adult mesenchymal stem cells (MSC) from the bone marrow of patients with a condition known as critical limb ischemia (CLI) a severe blockage of the arteries resulting in marked reduction in blood flow to the extremities.

Reduction in blood flow to the legs puts patients at risk of gangrene, ulceration, and amputation, and the Galway trial will look at the use of MSCs to grow new stems cells which will then be injected back into the patients leg with the hope of growing new blood cells and improving circulation.

The harvested stem cells will be grown to much greater quantities in a highly specialised lab before being injected back into the patients leg.

Tim OBrien, director of the Galway-based Regenerative Medicine Institute, said their research was focused on whether MSC therapy could improve blood flow to the legs in patients with CLI a condition common in diabetics and therefore avoid the need for amputation. The trial is aimed predominantly at testing the safety and feasibility of what is very much an experimental therapy, Prof OBrien said.

We will be doing a dose escalation study, with some patients given a small dose, others a medium dose and the remainder a high dose, he said. We want to try and establish how many cells do you need to give a patient.

The study, the first in humans in Ireland, will be a year-long study involving nine patients. Prof OBrien said they would not be advertising for participants, but rather would let clinicians know and await referrals of suitable patients.

In the meantime, they would be preparing the custom-built facility where the cells are grown, at the Centre for Cell Manufacturing Ireland in NUI Galway, the first such facility in Ireland to receive a licence from the Health Products Regulatory Authority.

Prof OBrien said MSCs have a lot of properties that may make them useful in treating a wide variety of disease because of their reparative and regenerative qualities.

Prof OBrien delivered a talk yesterday on the Therapeutic Potential of MSCs in Diabetic Complications on the second day of a two-day international stem cell conference at NUI Galway.

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Lab-grown stem cell trial gets green light

Bostons Adult Stem Cell Technology Center, LLC Introduces A New Technology for Monitoring Previously Elusive Adult …

Boston, MA (PRWEB) October 30, 2014

James Sherley says he has been working towards ASCTCs new advance in adult tissue stem cell technology since his days as a principal investigator at the Fox Chase Cancer Center (FCCC) in Philadelphia in the late 1990s. Sherley founded the ASCTC as a new Boston biotech start-up last year. The company holds all the intellectual property developed in Sherleys research over the years since FCCC, first as a professor at the Massachusetts Institute of Technology (MIT), and more recently as a senior scientist at the now closed Boston Biomedical Research Institute.

The basic concept for ASCTCs new technology was first published in 2001, after Sherleys arrival to MIT in 1998. The report introduced the new concept that the characteristic limited cell output of human tissue cell cultures was caused entirely by the special multiplication pattern of adult stem cells in the cultures known as asymmetric cell kinetics. Sherley recounts, My idea was pretty much ignored by everyone, because of a very popular ten-years older hypothesis to explain the short growth period of human cell cultures. The preexisting explanation, which was based on the concept of shortening chromosome ends, called telomeres, is still widely accepted today.

At the time of its first report, Sherleys asymmetric cell kinetics theoretical concept was lacking a quantitative model that could be used to test it. This situation began to change in the summer of 2011, when he met Dr. Frank Abdi, Chief Scientist of the Long Beach California company AlphaSTAR Corporation (ASC). The two were at a research conference organized to bring engineers and biologists together to inspire interdisciplinary research in the new field of bio-mesomechanics.

ASC develops computer simulation analyses to predict the physical failure of complex composite materials used to build aircraft, racing cars, and other high stress transports like the space shuttle. In the ensuing period after the 2011 introduction, ASCTC was founded, and the two companies integrated their respective expertise to produce the first-of-its-kind quantitative asymmetric stem cell kinetics model for human tissue cell cultures.

During its development, Sherley has described the concept for the new technology in brief in biotechnology and pharmaceutical industry forums. However, his talk at the Novel Stem Cells & Vesicles Symposium, organized at Rhode Island Hospital by Brown Universitys National Institutes of Health Stem Cell Biology Center of Biomedical Research Excellence (COBRE), will be the first presentation in an academic research forum. Dr. Sherley will discuss how the asymmetric stem cell kinetics model not only quantitatively accounts for human cell culture properties, but also accounts for features for which the telomerase shortening concept cannot.

By defining human cell culture output in terms of the specific actions of adult tissue stem cells, the new technology provides an exciting new tool for drug development and regenerative medicine. It gives the capability to monitor adult stem cell number, which previously has not been possible. The ability to monitor stem cell number opens a long closed door to many important biomedical applications. These include identifying drugs that would be harmful because of toxicity against tissue stem cells; identifying drugs that might improve normal tissue stem cells repair function; identifying new cancer drugs that attack aberrant cancer tissue stem cells; and providing a means to determine the number of stem cells needed for successful stem cell transplants (e.g., blood stem cell transplants).

As a first commercial target, ASCTC and ASC are developing the new technologys ability to provide an early screen for drug candidates that would fail later at more expensive places along the drug development pipeline due to tissue stem cell toxicity. Toxicity against tissue stem cells is one of the most devastating forms of drug toxicity. The new technology could save the U.S. pharmaceutical industry as much as $4 billion of the estimated $40 billion that it spends on failed drug candidates each year. Besides reducing cost and accelerating development of needed new drugs, the new tissue stem cell monitoring technology would also reduce the exposure of patients to particularly harmful drug candidates.

******************************************************************************************** The Adult Stem Cell Technology Center, LLC (ASCTC) is a Massachusetts life sciences company established in September 2013. ASCTC Director and founder, James L. Sherley, M.D., Ph.D. is the foremost authority on the unique properties of adult tissue stem cells. The companys patent portfolio contains biotechnologies that solve the three main technical problems production, quantification, and monitoring that have stood in the way of successful commercialization of human adult tissue stem cells for regenerative medicine and drug development. In addition, the portfolio includes novel technologies for isolating cancer stem cells and producing induced pluripotent stem cells. Currently, ASCTC is employing its technological advantages to pursue commercialization of mass-produced therapeutic human liver cells and facile assays that are early warning systems for drug candidates with catastrophic toxicity due to adverse effects against adult tissue stem cells.

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Identifying the source of stem cells

7 hours ago Amy Ralston, MSU biochemist and molecular biologist, has identified a possible source of stem cells, which can advance regenerative and fertility research. Credit: G.L. Kohuth

When most animals begin life, cells immediately begin accepting assignments to become a head, tail or a vital organ. However, mammals, including humans, are special. The cells of mammalian embryos get to make a different first choice to become the protective placenta or to commit to forming the baby.

It's during this critical first step that research from Michigan State University has revealed key discoveries. The results, published in the current issue of PLOS Genetics, provide insights into where stem cells come from, and could advance research in regenerative medicine. And since these events occur during the first four or five days of human pregnancy, the stage in which the highest percentage of pregnancies are lost, the study also has significant implications for fertility research.

Pluripotent stem cells can become any cell in the body and can be created in two ways. First, they can be produced when scientists reprogram mature adult cells. Second, they are created by embryos during this crucial four-day window of a mammalian pregnancy. In fact, this window is uniquely mammalian, said Amy Ralston, MSU assistant professor of biochemistry and molecular biology, and lead author on the study.

"Embryos make pluripotent stem cells with 100 percent efficiency," she said. "The process of reprogramming cells, manipulating our own cells to become stem cells, is merely 1 percent efficient. Embryos have it figured out, and we need to learn how they're doing it."

The researchers' first discovery is that in mouse embryos, the gene, Sox2, appears to be acting ahead of other genes traditionally identified as playing crucial roles in stem cell formation. Simply put, this gene could determine the source of stem cells in mammals. Now researchers are trying to decipher why Sox2 is taking the lead role.

"Now we know Sox2 is the first indicator that a cell is pluripotent," Ralston said. "In fact, Sox2 may be the pre-pluripotent gene. We show that Sox2 is detectable in just one or two cells of the embryo earlier than previously thought, and earlier than other known stem cell genes."

The second discovery is that Sox2 has broader influence than initially thought. The gene appears to help coordinate the cells that make the fetus and the other cells that establish the pregnancy and nurture the fetus.

Future research will focus on studying exactly why Sox2 is playing this role. The team has strong insights, but they want to go deeper, Ralston said.

"Reprogramming is amazing, but it's inefficient," she said. "What we've learned from the embryo is how to improve efficiency, a process that could someday lead to generating stem cells for clinical purposes with a much higher success rate."

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Identifying the source of stem cells