QNRF Newsletter Archive

Researchers working to usher in a new paradigm of stem cell therapy

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(Click image to enlarge) Hematopoietc stem cells (green arrows) and endothelial cells in the placenta (yellow arrow). From Raynaud et al. (under preparation)
Because of their ability to become any type of cell in the body and potentially restore damaged tissues, stem cells have long been the focus of research. Yet progress in the field of stem-cell-based regenerative medicine has all but reached a stand still. The two main focal points of this research—embryonic stem cells and induced pluripotent stem (IPS) cells—have not yet reached consistency in terms of their ability to produce disease-free cells that regrow organ tissue. Researchers based in New York City and Doha are working on an approach that involves the endothelial cells that make up the vascular system as a supportive "niche" for growing stem cells.

"Endothelial cells are the mother load,” said Shahin Rafii, Arthur B. Belfer Professor of Genetic and Regenerative Medicine at Weill Cornell Medical College in New York and one of the lead investigators on this unique approach to regenerative stem cell therapy. "They produce growth factors. They produce cytokines. They produce enablers and enzymes to make organs regenerate. This applies to every stem cell in your body whether its brain, or heart muscle … endothelial cells are not just a conduit to deliver nutrients or oxygen, they directly support organ regeneration."

Several years ago, Dr. Rafii discovered a key technique that promotes the stability of endothelial cells and allows them to produce angiocrine factors contributing to the establishment of a "vascular niche." The technique involves inserting part of a virus into the endothelial cell so that it over-expressed a protein that supports and stabilizes the niche for stem cell growth. In essence the endothelium through the over-expression of the protein becomes an active producer of substances that support growth in a direction specific to the endothelial cells of the organ.

"In developmental systems, endothelial cells precede the organ," said Dr. Jeremie Arash Rafii Tabrizi, Associate Professor of Genetic Medicine at Weill Cornell Medical College in Qatar and collaborator on this QNRF National Priorities Research Program-funded research into endothelial stem cell niche therapy. "Whether in the liver or lung, the organs usually form around endothelial cells that act as a niche. Before the growth of organs and even before the settlement of a blood flow, endothelial cells have a role in promoting the constitution of an organ."

In the case of IPS and embryonic cells, the stem cells either do not proliferate, contain the potential to form tumors or grow in an unstable way, wherein they “drift,” i.e., become other types of cells than those of the target organ or tissue.

"It’s going to be a long time before we can harness the potential of IPS or embryonic derived stem cells," said Dr. Rafii. "Cellular derivatives of IPS and the cellular derivatives of embryonic stem cells are very unstable."

Stepping back and working with the niche to support the stem cell growth in a stable, natural environment is where the team hopes to make significant progress in regenerative medicine. For example, Dr. Rafii Tabrizi explained that hematopoietic (blood stem) cells produce countless platelets and white blood cells on a daily basis and these cells are produced consistently. The stability of their production is due to the microscopic endothelial niche that supports the hematopoietic cells. Work has been conducted in the bone marrow and placenta to further explore the potential for endothelial cells to enhance stable and prolific growth of stem cells. The results have been promising.

"Actually we have proven it works with animals," Dr. Rafii explained. "Now we need funding to move it to humans, to transplant the organ-specific endothelium, optimize its capacity for damaged tissue, optimize its capacity to produce growth factors optimize its capacity to prevent fibrotic changes as the organ heals. This is just the beginning of a major endeavor for the next ten years."

Research into cancer tumor formation has contributed to the understanding of the endothelial niche as well, Dr. Rafii Tabrizi said. Although researchers have been looking from the perspective of breaking up the blood vessels and stopping the growth of tissues, they are still honing in on the mechanisms at play in the endothelial niche.

"So this platform is very powerful," he said. "Because in one respect we can understand how we can use endothelium to regenerate and in another we can understand how the endothelium is used by tumors to grow so that we can try to target this aspect. The same cues that are used in development of tissues are usually hijacked by cancer cells, so understanding them in one setting can help us prevent them."

The research team is in the process of applying for an NPRP-Exceptional Program grant in collaboration with renowned surgeon, Dr. Magdi Yacoub, Professor of Cardiothoracic Surgery at Imperial College London, who has access to many patients who are in a chronic state due to complications of diabetes.

"In Qatar one of the biggest health problems is diabetes," Dr. Rafii Tabrizi said, "and one of the aspects of diabetes is a chronic state of hypoperfusion (decreased blood flow to an organ), especially in the legs. In this case the nerve dies and the vessels die."

These complications often result in amputations. The team sees these cases as a chance to apply endothelial therapy, which could potentially restore the tissue not only through restoring blood flow but also by delivering the appropriate growth factors.

"The evidence we’ve built is prompting us to move fast," Dr. Rafii Tabrizi said. "It is really great that QNRF has already supported our studies—they’ve shown a real eagerness to fund real innovative research. The major achievement will not only come from good publications but also from our ability to translate findings into patient care. This will be a major achievement for Qatar."

NPRP 08-663-3–140 :
Stage Specific Differentiation of Pluripotent Stem Cells into Functional Hemangiogenic Tissues 
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