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Blood from stem cells
05-23-2017
by Kelsey Kaustinen  |  Email the author
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NEW YORK—Blood donors, like organ donors, are always in demand--not just for regular transfusions, but also for the treatment of diseases such as leukemia, kidney or liver disease and hemophilia, among others. Renewable sources of healthy blood, specifically those which could be replicated in the lab and matched safely with patients, represent a goal line that has long been out of reach.
 
That goal is one step closer now, though, as a team at Weill Cornell Medicine has developed and demonstrated a technique for generating healthy blood cells by reprogramming endothelial cells—a first for any research team. The results of this work were published in a paper titled "Conversion of adult endothelium to immunocompetent hematopoietic stem cells," which appeared in Nature.
 
“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.
 
Hematopoietic stem cells (HSCs) are long-lived cells that develop into all types of blood cells, while circulating blood cells have short lifespans and must be continuously reproduced. HSCs are capable of “self renewal” to create more of themselves, which enables a few thousand of these cells to generate all of an individual's blood cells throughout their life. Work to coerce the body into producing healthy HSCs has failed in the past due to an inability to create the proper environment, but that is a problem that might have finally been solved by the Weill Cornell team.
 
The researchers were able to develop a technique that converts vascular endothelial cells, which line blood vessels, into fully functioning HSCs that can be transplanted. In addition, they found that certain types of endothelial cells serve as vascular niche cells, the nurturing environment needed for HSCs to develop; these cells coordinate the new, converted HSCs' ability of self-renewal.
 
Rafii's lab has a history of work with endothelial cells in various parts of the body. As noted on his faculty page, Rafii "has established the concept that vascular endothelial cells are not just inert plumbing to deliver oxygen and nutrients, but also by production of tissue-specific growth factors, defined as angiocrine factors, support organ regeneration and tumor proliferation. He has shown that bone marrow endothelial cells by elaboration of angiocrine factors, such as Notch ligands, support stem cell self-renewal and differentiation into lymphoid and myeloid progenitors. He has recently demonstrated that liver and lung endothelial cells are endowed with unique phenotypic and functional attributes and by production of unique instructive growth factors contribute to the hepatic and alveolar regeneration."
 
“We think the difference is the vascular niche,” contributing author Dr. Jason Butler, an assistant professor of regenerative medicine at Weill Cornell Medicine, commented in a press release. “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.”
 
Efforts in this field have been underway for several years. In a 2014 Nature study, the team demonstrated that it was possible to convert adult human vascular endothelial cells into hematopoietic cells, though they couldn't prove that had engineered HSCs. This time around, the researchers used their conversion approach on mouse blood marrow transplant models featuring normal immune function. Vascular endothelial cells isolated from adult mice organs were programmed to overproduce proteins linked with blood stem-cell function, then grown and multiplied in co-culture with the engineered vascular niche. The cells, now reprogrammed HSCs, were transplanted as single cells with their 'offspring'—which included white and red blood cells and immune cells—into mice with no blood-forming or immune systems to isolate their results.
 
Rafii and his colleagues, 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, were able to demonstrate that the reprogrammed HSCs and their differentiated progeny cells had the same genetic attributes as normal adult stem cells. In addition, the transplanted HSCs were able to regenerate the entire blood system in the model mice for the duration of their lifetimes, also known as engraftment, and the mice developed all the working features of the immune system. The mice in question also lived normal-length lives with no sign of any blood disorders.
 
As the authors noted in their abstract, “The vascular niche drives a robust self-renewal and expansion phase of rEC-HSCs (days 20–28). rEC-HSCs [reprogramming adult mouse endothelial cells to hematopoietic stem cells] have a transcriptome and long-term self-renewal capacity similar to those of adult hematopoietic stem cells, and can be used for clonal engraftment and serial primary and secondary multi-lineage reconstitution, including antigen-dependent adaptive immune function.”
 
The team is highly optimistic about the potential for this approach, should they be able to recreate it in humans.
 
“It might allow us to provide healthy stem cells to patients who need bone marrow donors but have no genetic match,” said co-senior author Dr. Joseph Scandura, an associate professor of medicine and scientific director of the Silver Myeloproliferative Neoplasms Center at Weill Cornell Medicine. “It could lead to new ways to cure leukemia and myeloproliferative neoplasms, 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,” added Rafii. “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.”
 
 
SOURCE: Weill Cornell Medicine press release
 
Code: E05241703

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