A study published on May 17 in Nature, discovers an innovative method to produce infinite supply of healthy blood cells from the readily available cells that line blood vessels. This achievement by the researchers at Weill Cornell Medicine marks the first time that any research group has generated such blood-forming stem cells.
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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 commented: "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,"
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."
Co-senior author Dr. Joseph Scandura, an associate professor of medicine and scientific director at 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. Blood cells do not survive for long in the body and must be constantly replaced. Severe blood diseases, such as anemia, bleeding or life-threatening infections, can occur when the blood cells are not continuously replenished. The self-renewal property of HSCs means that they have the ability to form more HSCs, which means that just a few thousand HSCs are needed to produce all of the blood cells a person has throughout one’s life.
In order to cure these diseases, researchers have long hoped to discover a method to make the body produce healthy HSCs. However, this has not been accomplished partly because until now scientists have not been able to engineer a fostering atmosphere in which stem cells can get converted into new and long-lasting cells.
Dr. Rafii and his team show a method to efficiently convert vascular endothelial cells, cells that line all blood vessels, into plenty of fully functioning HSCs that can be transplanted to yield new, healthy blood cells for a lifetime. The research team also discovered that specific types of endothelial cells—vascular niche cells - compose the self-renewal of the newly converted HSCs. This research may answer one of the most longstanding questions in regenerative and reproductive medicine: How do stem cells constantly replenish their supply?
In a previous study published in Nature in 2014, the research team showed the feasibility of converting adult human vascular endothelial cells into hematopoietic cells. Yet the team was not able to prove the generation of true HSCs as the function of human HSCs and regenerative potential can only be approximated by transplanting the cells into mice—which did not truly imitate human biology.
In order to address this issue, the team applied their approach to blood marrow transplants in a mouse model, whereby the definitive evidence for HSC potential could be rigorously tested, as the mouse blood transplant models were endowed with normal immune function. The vascular endothelial cells isolated from readily accessible organs of the adult mice were taken and the researchers instructed them to produce more of certain proteins connected with the functioning of the blood stem-cells.
These reprogrammed cells were developed 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. They were observed to see the possibility of self-renewal and production of healthy blood cells.
Surprisingly, the conversion process yielded transplantable HSCs in surplus that restored the entire blood system in mice for the duration of their lifetime—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, all of the working components of the immune systems are developed in the HSC-engrafted mice. "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 lived a normal life with no sign of leukemia or any other blood disorders and died of natural cause.
Dr. Rafii and his team 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 also demonstrated that the reprogrammed HSCs and their differentiated progenies involving the white and red bloods cells, as well as the immune cells were endowed with the same genetic attributes to that of normal stem cells of adults. These findings put forward that the consequences of the reprogramming process 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 accomplish cellular reprogramming for creating engraftable and authentic HSCs—considered to be 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."
This method could have wide-ranging clinical implications when scaled up and applied to human beings. "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."
Dr. Joseph Scandura, Silver Myeloproliferative Neoplasms Center at Weill Cornell Medicine
"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."