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Researchers at Weill Cornell Medicine have discovered an innovative method to make an unlimited supply of healthy blood cells from the readily available cells that line blood vessels. This achievement marks the first time that any research group has generated such blood-forming stem cells. "This is a game-changing breakthrough that brings us closer not only to treat blood disorders, but also deciphering the complex biology of stem-cell self-renewal machinery," said senior author Dr. Shahin Rafii, director of the Ansary Stem Cell Institute, chief of the Division of Regenerative Medicine and the Arthur B. Belfer Professor at Weill Cornell Medicine. "This is exciting because it provides us with a path towards generating clinically useful quantities of normal stem cells for transplantation that may help us cure patients with genetic and acquired blood diseases," added co-senior author Dr. Joseph Scandura, an associate professor of medicine and scientific director of the Silver Myeloproliferative Neoplasms Center at Weill Cornell Medicine. Hematopoietic stem cells (HSCs) are long-lasting cells that mature into all types of blood cells: white blood cells, red blood cells and platelets. Billions of circulating blood cells do not survive long in the body and must be continuously replenished. When this does not happen, severe blood diseases, such as anemia, bleeding or life-threatening infections, can occur. A special property of HSCs is that they can also "self-renew" to form more HSCs. This property allows just a few thousand HSCs to produce all of the blood cells a person has throughout one's life. Researchers have long hoped to find a way to make the body produce healthy HSCs in order to cure these diseases. But this has never been accomplished, in part because scientists have been unable to engineer a nurturing environment within which stem cells can convert into new, long-lasting cells--until now. In a paper published May 17 in Nature, Dr. Rafii and his colleagues demonstrate a way to efficiently convert cells that line all blood vessels, called vascular endothelial cells, into abundant, fully functioning HSCs that can be transplanted to yield a lifetime supply of new, healthy blood cells. The research team also discovered that specialized types of endothelial cells serve as that nurturing environment, known as vascular niche cells, and they choreograph the new converted HSCs' self-renewal. This finding may solve one of the most longstanding questions in regenerative and reproductive medicine: How do stem cells constantly replenish their supply? The research team showed in a 2014 study that converting adult human vascular endothelial cells into hematopoietic cells was feasible. However, the team was unable to prove that they had generated true HSCs because human HSCs' function and regenerative potential can only be approximated by transplanting the cells into mice, which don't truly mimic human biology. To address this issue, the team applied their conversion approach to mouse blood marrow transplant models that are endowed with normal immune function and where definitive evidence for HSC potential could rigorously tested. The researchers took vascular endothelial cells isolated from readily accessible adult mice organs and instructed them to overproduce certain proteins associated with blood stem-cell function. These reprogrammed cells were grown and multiplied in co-culture with the engineered vascular niche. The reprogrammed HSCs were then transplanted as single cells with their progenies into mice that had been irradiated to destroy all of their blood forming and immune systems, and then monitored to see whether or not they would self-renew and produce healthy blood cells. Remarkably, the conversion procedure yielded a plethora of transplantable HSCs that regenerated the entire blood system in mice for the duration of their lifespans, a phenomenon known as engraftment. "We developed a fully-functioning and long-lasting blood system," said lead author Dr. Raphael Lis, an instructor in medicine and reproductive medicine at Weill Cornell Medicine. In addition, the HSC-engrafted mice developed all of the working components of the immune systems. "This is clinically important because the reprogrammed cells could be transplanted to allow patients to fight infections after marrow transplants," Dr. Lis said. The mice in the study went on to live normal-length lives and die natural deaths, with no sign of leukemia or any other blood disorders. In collaboration with Dr. Olivier Elemento, associate director of the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine, and Dr. Jenny Xiang, the director of Genomics Services, Dr. Rafii and his team also showed that the reprogrammed HSCs and their differentiated progenies -- including white and red bloods cells, as well as the immune cells -- were endowed with the same genetic attributes to that of normal adult stem cells. These findings suggest that the reprogramming process results in the generation of true HSCs that have genetic signature that are very similar to normal adult HSCs The Weill Cornell Medicine team is the first to achieve cellular reprogramming to create engraftable and authentic HSCs, which have been considered the holy grail of stem cell research. "We think the difference is the vascular niche," said contributing author Dr. Jason Butler, an assistant professor of regenerative medicine at Weill Cornell Medicine. "Growing stem cells in the vascular niche puts them back into context, where they come from and multiply. We think this is why we were able to get stem cells capable of self-renewing." If this method can be scaled up and applied to humans, it could have wide-ranging clinical implications. "It might allow us to provide healthy stem cells to patients who need bone marrow donors but have no genetic match," Dr. Scandura said. "It could lead to new ways to cure leukemia, and may help us correct genetic defects that cause blood diseases like sickle-cell anemia." "More importantly, our vascular niche-stem-cell expansion model may be employed to clone the key unknown growth factors produced by this niche that are essential for self-perpetuation of stem cells," Dr. Rafii said. "Identification of those factors could be important for unraveling the secrets of stem cells' longevity and translating the potential of stem cell therapy to the clinical setting." Additional study co-authors include Charles Karrasch, Dr. Michael Poulos, Balvir Kunar, David Redmond, Jose-Gabriel Barcia-Duran, Chaitanya Badwe, and Koji Shido of Weill Cornell Medicine; Dr. Will Schachterle, formerly of Weill Cornell Medicine, Dr. Arash Rafii of Weill Cornell Medicine-Qatar; Dr. Michael Ginsberg of Angiocrine Bioscience; and Dr. Nancy Speck of the Abramson Family Cancer Research Institute in the Perelman School of Medicine at the University of Pennsylvania. Various study authors have relationships with Angiocrine Bioscience that are independent of Weill Cornell Medicine. This study was funded in part by the National Institutes of Health, grants NIH-R01 DK095039, HL119872, HL128158, HL115128, HL099997, CA204308, HL133021, HL119872, HL128158 and HL091724; U54 CA163167; and NIH-T32 HD060600.


News Article | May 18, 2017
Site: www.sciencedaily.com

Researchers at Weill Cornell Medicine have discovered an innovative method to make an unlimited supply of healthy blood cells from the readily available cells that line blood vessels. This achievement marks the first time that any research group has generated such blood-forming stem cells. "This is a game-changing breakthrough that brings us closer not only to treat blood disorders, but also deciphering the complex biology of stem-cell self-renewal machinery," said senior author Dr. Shahin Rafii, director of the Ansary Stem Cell Institute, chief of the Division of Regenerative Medicine and the Arthur B. Belfer Professor at Weill Cornell Medicine. "This is exciting because it provides us with a path towards generating clinically useful quantities of normal stem cells for transplantation that may help us cure patients with genetic and acquired blood diseases," added co-senior author Dr. Joseph Scandura, an associate professor of medicine and scientific director of the Silver Myeloproliferative Neoplasms Center at Weill Cornell Medicine. Hematopoietic stem cells (HSCs) are long-lasting cells that mature into all types of blood cells: white blood cells, red blood cells and platelets. Billions of circulating blood cells do not survive long in the body and must be continuously replenished. When this does not happen, severe blood diseases, such as anemia, bleeding or life-threatening infections, can occur. A special property of HSCs is that they can also "self-renew" to form more HSCs. This property allows just a few thousand HSCs to produce all of the blood cells a person has throughout one's life. Researchers have long hoped to find a way to make the body produce healthy HSCs in order to cure these diseases. But this has never been accomplished, in part because scientists have been unable to engineer a nurturing environment within which stem cells can convert into new, long-lasting cells -- until now. In a paper published May 17 in Nature, Dr. Rafii and his colleagues demonstrate a way to efficiently convert cells that line all blood vessels, called vascular endothelial cells, into abundant, fully functioning HSCs that can be transplanted to yield a lifetime supply of new, healthy blood cells. The research team also discovered that specialized types of endothelial cells serve as that nurturing environment, known as vascular niche cells, and they choreograph the new converted HSCs' self-renewal. This finding may solve one of the most longstanding questions in regenerative and reproductive medicine: How do stem cells constantly replenish their supply? The research team showed in a 2014 Nature study that converting adult human vascular endothelial cells into hematopoietic cells was feasible. However, the team was unable to prove that they had generated true HSCs because human HSCs' function and regenerative potential can only be approximated by transplanting the cells into mice, which don't truly mimic human biology. To address this issue, the team applied their conversion approach to mouse blood marrow transplant models that are endowed with normal immune function and where definitive evidence for HSC potential could rigorously tested. The researchers took vascular endothelial cells isolated from readily accessible adult mice organs and instructed them to overproduce certain proteins associated with blood stem-cell function. These reprogrammed cells were grown and multiplied in co-culture with the engineered vascular niche. The reprogrammed HSCs were then transplanted as single cells with their progenies into mice that had been irradiated to destroy all of their blood forming and immune systems, and then monitored to see whether or not they would self-renew and produce healthy blood cells. Remarkably, the conversion procedure yielded a plethora of transplantable HSCs that regenerated the entire blood system in mice for the duration of their lifespans, a phenomenon known as engraftment. "We developed a fully-functioning and long-lasting blood system," said lead author Dr. Raphael Lis, an instructor in medicine and reproductive medicine at Weill Cornell Medicine. In addition, the HSC-engrafted mice developed all of the working components of the immune systems. "This is clinically important because the reprogrammed cells could be transplanted to allow patients to fight infections after marrow transplants," Dr. Lis said. The mice in the study went on to live normal-length lives and die natural deaths, with no sign of leukemia or any other blood disorders. In collaboration with Dr. Olivier Elemento, associate director of the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine, and Dr. Jenny Xiang, the director of Genomics Services, Dr. Rafii and his team also showed that the reprogrammed HSCs and their differentiated progenies -- including white and red bloods cells, as well as the immune cells -- were endowed with the same genetic attributes to that of normal adult stem cells. These findings suggest that the reprogramming process results in the generation of true HSCs that have genetic signature that are very similar to normal adult HSCs The Weill Cornell Medicine team is the first to achieve cellular reprogramming to create engraftable and authentic HSCs, which have been considered the holy grail of stem cell research. "We think the difference is the vascular niche," said contributing author Dr. Jason Butler, an assistant professor of regenerative medicine at Weill Cornell Medicine. "Growing stem cells in the vascular niche puts them back into context, where they come from and multiply. We think this is why we were able to get stem cells capable of self-renewing." If this method can be scaled up and applied to humans, it could have wide-ranging clinical implications. "It might allow us to provide healthy stem cells to patients who need bone marrow donors but have no genetic match," Dr. Scandura said. "It could lead to new ways to cure leukemia, and may help us correct genetic defects that cause blood diseases like sickle-cell anemia." "More importantly, our vascular niche-stem-cell expansion model may be employed to clone the key unknown growth factors produced by this niche that are essential for self-perpetuation of stem cells," Dr. Rafii said. "Identification of those factors could be important for unraveling the secrets of stem cells' longevity and translating the potential of stem cell therapy to the clinical setting."


New research has nudged scientists closer to one of regenerative medicine’s holy grails: the ability to create customized human stem cells capable of forming blood that would be safe for patients. Advances reported Wednesday in the journal Nature could not only give scientists a window on what goes wrong in such blood cancers as leukemia, lymphoma and myeloma. They could also improve the treatment of those cancers, which affect some 1.2 million Americans. The stem cells that give rise to our blood are a mysterious wellspring of life. In principle, just one of these primitive cells can create much of a human being’s immune system, not to mention the complex slurry of cells that courses through a person’s arteries, veins and organs. While the use of blood-making stem cells in medicine has been common since the 1950s, it remains pretty crude. After patients with blood cancers have undergone powerful radiation and chemotherapy treatments to kill their cancer cells, they often need a bone-marrow transplant to rebuild their white blood cells, which are destroyed by that treatment. The blood-making stem cells that reside in a donor’s bone marrow — and in umbilical cord blood that is sometimes harvested after a baby’s birth — are called “hematopoietic,” and they can be life-saving. But even these stem cells can bear the distinctive immune system signatures of the person from whom they were harvested. As a result, they can provoke an attack if the transplant recipient’s body registers the cells as foreign. This response, called graft-versus-host disease, affects as many as 70% of bone-marrow transplant recipients in the months following the treatment, and 40% develop a chronic version of the affliction later. It can overwhelm the benefit of a stem cell transplant. And it kills many patients. Rather than hunt for a donor who’s a perfect match for a patient in need of a transplant — a process that can be lengthy, ethically fraught and ultimately unsuccessful — doctors would like to use a patient’s own cells to engineer the hematopoietic stem cells. The patient’s mature cells would be “reprogrammed” to their most primitive form: stem cells capable of becoming virtually any kind of human cell. Then factors in their environment would coax them to become the specific type of stem cells capable of giving rise to blood. Once reintroduced into the patient, the cells would take up residence without prompting rejection and set up a lifelong factory of healthy new blood cells. If the risk of deadly rejection episodes could be eliminated, physicians might also feel more confident treating blood diseases that are painful and difficult but not immediately deadly — diseases such as sickle cell disease and immunological disorders — with stem cell transplants. The two studies published Wednesday demonstrate that scientists may soon be capable of pulling off the sequence of operations necessary for such treatments to move ahead. One of two research teams, led by stem-cell pioneer Dr. George Q. Daley of Harvard Medical School and the Dana Farber Cancer Institute in Boston, started their experiment with human “pluripotent” stem cells — primitive cells capable of becoming virtually any type of mature cell in the body. Some of them were embryonic stem cells and others were induced pluripotent stem cells, or iPS cells, which are made by converting mature cells back to a flexible state. The scientists then programmed those pluripotent stem cells to become endothelial cells, which line the inside of certain blood vessels. Past research had established that those cells are where blood-making stem cells are born. Here, the process needed a nudge. Using suppositions gleaned from experiments with mice, Daley said his team confected a “special sauce” of proteins that sit on a cell’s DNA and program its function. When they incubated the endothelial cells in the sauce, they began producing hematopioetic stem cells in their earliest form. Daley’s team then transferred the resulting blood-making stem cells into the bone marrow of mice to see if they would “take.” In two out of five mice who got the most promising cell types, they did. Not only did the stem cells establish themselves, they continued to renew themselves while giving rise to a wide range of blood cells. A second research team, led by researchers from Weill Cornell Medicine’s Ansary Stem Cell Institute in New York, achieved a similar result using stem cells from the blood-vessel lining of adult mice. After programming those cells to revert to a more primitive form, the scientists also incubated those stem cells in a concoction of specialized proteins. When the team, led by Raphael Lis and Dr. Shahin Rafii, transferred the resulting stem cells back into the tissue lining the blood vessels of the mice from which they came, that graft also “took.” For at least 40 weeks after the incubated stem cells were returned to their mouse owners, the stem cells continued to regenerate themselves and give rise to many blood-cell types without provoking immune reactions. In addition to making a workhorse treatment for blood cancers safer, the new advances may afford scientists a unique window on the mechanisms by which blood diseases take hold and progress, said Lee Greenberger, chief scientific officer for the Leukemia and Lymphoma Society. “From a research point of view you could now actually begin to model diseases,” said Greenberger. “If you were to take the cell that’s defective and make it revert to a stem cell, you could effectively reproduce the disease and watch its progression from the earliest stages.” That, in turn, would make it easier to narrow the search for drugs that could disrupt that disease process early. And it would speed the process of discovering which genes are implicated in causing diseases. With gene-editing techniques such as CRISPR-Cas9, those offending genes could one day be snipped out of hematopoietic stem cells, then be returned to their owners to generate new lines of disease-free blood cells.


PubMed | Weill Cornell Medicine, Ansary Stem Cell Institute and New York University
Type: Journal Article | Journal: Cancer cell | Year: 2016

Tumor-associated endothelial cells (TECs) regulate tumor cell aggressiveness. However, the core mechanism by which TECs confer stem cell-like activity to indolent tumors is unknown. Here, we used invivo murine and human tumor models to identify the tumor-suppressive checkpoint role of TEC-expressed insulin growth factor (IGF) binding protein-7 (IGFBP7/angiomodulin). During tumorigenesis, IGFBP7 blocks IGF1 and inhibits expansion and aggresiveness of tumor stem-like cells (TSCs) expressing IGF1 receptor (IGF1R). However, chemotherapy triggers TECs to suppress IGFBP7, and this stimulates IGF1R


Liu Y.,Ansary Stem Cell Institute | Liu Y.,Rockefeller University | Giannopoulou E.G.,New York City College of Technology | Giannopoulou E.G.,Hospital for Special Surgery | And 6 more authors.
Nature Communications | Year: 2016

Spermatogonial stem and progenitor cells (SSCs) generate adult male gametes. During in vitro expansion, these unipotent murine cells spontaneously convert to multipotent adult spermatogonial-derived stem cells (MASCs). Here we investigate this conversion process through integrative transcriptomic and epigenomic analyses. We find in SSCs that promoters essential to maintenance and differentiation of embryonic stem cells (ESCs) are enriched with histone H3-lysine4 and-lysine 27 trimethylations. These bivalent modifications are maintained at most somatic promoters after conversion, bestowing MASCs an ESC-like promoter chromatin. At enhancers, the core pluripotency circuitry is activated partially in SSCs and completely in MASCs, concomitant with loss of germ cell-specific gene expression and initiation of embryonic-like programs. Furthermore, SSCs in vitro maintain the epigenomic characteristics of germ cells in vivo. Our observations suggest that SSCs encode innate plasticity through the epigenome and that both conversion of promoter chromatin states and activation of cell type-specific enhancers are prominent features of reprogramming.


Nolan D.,Howard Hughes Medical Institute | Nolan D.,Angiocrine Bioscience | Ginsberg M.,Howard Hughes Medical Institute | Ginsberg M.,Angiocrine Bioscience | And 18 more authors.
Developmental Cell | Year: 2013

Microvascular endothelial cells (ECs) within different tissues are endowed with distinct but as yet unrecognized structural, phenotypic, and functional attributes. We devised EC purification, cultivation, profiling, and transplantation models that establish tissue-specific molecular libraries of ECs devoid of lymphatic ECs or parenchymal cells. These libraries identify attributes that confer ECs with their organotypic features. We show that clusters of transcription factors, angiocrine growth factors, adhesion molecules, and chemokines are expressed in unique combinations by ECs of each organ. Furthermore, ECs respond distinctly in tissue regeneration models, hepatectomy, and myeloablation. To test the data set, we developed a transplantation model that employs generic ECs differentiated from embryonic stem cells. Transplanted generic ECs engraft into regenerating tissues and acquire features of organotypic ECs. Collectively, we demonstrate the utility of informational databases of ECs toward uncovering the extravascular and intrinsic signals that define EC heterogeneity. These factors could be exploited therapeutically to engineer tissue-specific ECs for regeneration. © 2013 Elsevier Inc.


PubMed | Angiocrine Bioscience, Ansary Stem Cell Institute and New York Medical College
Type: | Journal: Nature communications | Year: 2017

Transplanting vascular endothelial cells (ECs) to support metabolism and express regenerative paracrine factors is a strategy to treat vasculopathies and to promote tissue regeneration. However, transplantation strategies have been challenging to develop, because ECs are difficult to culture and little is known about how to direct them to stably integrate into vasculature. Here we show that only amniotic cells could convert to cells that maintain EC gene expression. Even so, these converted cells perform sub-optimally in transplantation studies. Constitutive Akt signalling increases expression of EC morphogenesis genes, including Sox17, shifts the genomic targeting of Fli1 to favour nearby Sox consensus sites and enhances the vascular function of converted cells. Enforced expression of Sox17 increases expression of morphogenesis genes and promotes integration of transplanted converted cells into injured vessels. Thus, Ets transcription factors specify non-vascular, amniotic cells to EC-like cells, whereas Sox17 expression is required to confer EC function.


PubMed | Copenhagen University, New York University, Rigshospitalet, Cornell University and 3 more.
Type: Journal Article | Journal: JCI insight | Year: 2016

Regeneration of hepatic sinusoidal vasculature is essential for non-fibrotic liver regrowth and restoration of its metabolic capacity. However, little is known about how this specialized vascular niche is regenerated. Here we show that activation of endothelial sphingosine-1-phosphate receptor-1 (S1P


Ginsberg M.,Angiocrine Bioscience | Schachterle W.,Ansary Stem Cell Institute | Shido K.,Ansary Stem Cell Institute | Rafii S.,Ansary Stem Cell Institute
Nature Protocols | Year: 2015

Endothelial cells (ECs) have essential roles in organ development and regeneration, and therefore they could be used for regenerative therapies. However, generation of abundant functional endothelium from pluripotent stem cells has been difficult because ECs generated by many existing strategies have limited proliferative potential and display vascular instability. The latter difficulty is of particular importance because cells that lose their identity over time could be unsuitable for therapeutic use. Here, we describe a 3-week platform for directly converting human mid-gestation lineage-committed amniotic fluid-derived cells (ACs) into a stable and expandable population of vascular ECs (rAC-VECs) without using pluripotency factors. By transient expression of the ETS transcription factor ETV2 for 2 weeks and constitutive expression the ETS transcription factors FLI1 and ERG1, concomitant with TGF-β inhibition for 3 weeks, epithelial and mesenchymal ACs are converted, with high efficiency, into functional rAC-VECs. These rAC-VECs maintain their vascular repertoire and morphology over numerous passages in vitro, and they form functional vessels when implanted in vivo. rAC-VECs can be detected in recipient mice months after implantation. Thus, rAC-VECs can be used to establish a cellular platform to uncover the molecular determinants of vascular development and heterogeneity and potentially represent ideal ECs for the treatment of regenerative disorders. © 2015 Nature America, Inc. All rights reserved.


PubMed | Angiocrine Bioscience and Ansary Stem Cell Institute
Type: Journal Article | Journal: Nature protocols | Year: 2015

Endothelial cells (ECs) have essential roles in organ development and regeneration, and therefore they could be used for regenerative therapies. However, generation of abundant functional endothelium from pluripotent stem cells has been difficult because ECs generated by many existing strategies have limited proliferative potential and display vascular instability. The latter difficulty is of particular importance because cells that lose their identity over time could be unsuitable for therapeutic use. Here, we describe a 3-week platform for directly converting human mid-gestation lineage-committed amniotic fluid-derived cells (ACs) into a stable and expandable population of vascular ECs (rAC-VECs) without using pluripotency factors. By transient expression of the ETS transcription factor ETV2 for 2 weeks and constitutive expression the ETS transcription factors FLI1 and ERG1, concomitant with TGF- inhibition for 3 weeks, epithelial and mesenchymal ACs are converted, with high efficiency, into functional rAC-VECs. These rAC-VECs maintain their vascular repertoire and morphology over numerous passages in vitro, and they form functional vessels when implanted in vivo. rAC-VECs can be detected in recipient mice months after implantation. Thus, rAC-VECs can be used to establish a cellular platform to uncover the molecular determinants of vascular development and heterogeneity and potentially represent ideal ECs for the treatment of regenerative disorders.

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