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Pluripotent Stem Cells Offer Blood Ready for Preclinical Trials

Posted January 26, 2016
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When the body has a low blood cell count, it can have trouble fighting off infection. But with the work of some of the University of Wisconsin-Madison’s brightest researchers, transfusible blood products may be in the not-so-distant future.

Igor Slukvin, professor of pathology and laboratory medicine, is the senior author of a new study published in Cell Press that outlines how his lab and others, including stem cell pioneer James Thomson, are ready to take skin cells from non-human primates and reengineer them in the lab to generate functional blood products ready to be reintroduced. Their work sets the stage for preclinical studies that could impact a number of clinical therapies for blood and immune system diseases.

For instance, undergoing a bone marrow transplant will leave your body a blank slate when it comes to your immune system. To transplant new bone marrow, physicians must first destroy some or all of the existing marrow to clear the way. This leaves patients who receive new bone marrow — often due to cancers like leukemias or lymphomas — without any way to naturally fight infections shortly after the transplant.

The new blood-producing, or hematopoietic, stem cells contained in the transplant take several weeks to grow and expand enough to normalize low blood cell counts, known as cytopenia, and restart the immune system. But in the meantime, the transplant recipient is very vulnerable to common infections, which in this weakened state could be fatal.

But what the Slukvin lab is suggesting could be used as a stopgap until the new hematopoietic stem cells can take over. By taking fully developed skin cells from a patient’s arm and reprogramming them back into stem cells, Slukvin and collaborators believe they can then turn the new induced pluripotent stem cells (iPSCs) into a variety of genetically identical or genetically matched blood products.

“When bone marrow is transplanted, there is a prolonged period of cytopenia, and especially low neutrophil (the most abundant white blood cell) counts,” said Slukvin, a researcher at the UW School of Medicine and Public Health. “We are looking to use iPS-derived blood cells to correct cytopenia during bone marrow suppression. Once we can get positive results in a preclinical model, we can move this into clinical trials with humans.”

Until now, most non-human primate iPSCs have been developed by borrowing the specialized mechanisms viruses use to deliver their genome into a host cells. But to be clinically relevant for humans, researchers needed a different way to reprogram cells because retrovirals leave behind foreign DNA. And while that’s not always dangerous, there’s no guarantee there won’t be unforeseen consequences down the road, so better safe than sorry. The Thomson lab pioneered footprint-free iPSCs from human cells. As noted in the study, his lab generated similar cells from non-human primates, allowing Slukvin to move forward with preclinical studies.

Perhaps the most important aspect of this work is that the Slukvin lab has developed a system to generate different types of blood cells — red blood cells, T cells, natural killer cells, myeloid cells like dendritic cells and neutrophils—from non-human primate-derived iPSCs. The cells were derived from rhesus and Chinese cynomolgus macaques, and a cell line from a Mauritian cynomolgus macaque.

Because non-human primates are very similar in physiology to humans, they represent the best model for preclinical trials of iPSC-derived blood products.

To move artificially created blood products into a clinical setting, researchers first will need to complete proof-of-concept studies and preclinical safety and toxicity studies of such stem cell therapies in animal models, as required by the US Food and Drug Administration.

Source: University of Wisconsin-Madison

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