Developmental biology

Promises broad clinical benefits, from bone marrow transplantation to therapies for heart, brain, skin and lungs. In a leap toward making stem cell therapy widely available, researchers at the Ansary Stem Cell Institute at Weill Cornell Medical College have discovered that endothelial cells, the most basic building blocks of the vascular system, produce growth factors that can grow copious amounts of adult stem cells and their progeny over the course of weeks. Until now, adult stem cell cultures would die within four or five days despite best efforts to grow them.

“This is groundbreaking research with potential application for regeneration of organs and inhibition of cancer cell growth,” said Dr. Antonio M. Gotto Jr., the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College and Provost for Medical Affairs of Cornell University. “We are indebted to Shahla and Hushang Ansary for founding this Institute and to the Starr Foundation Tri-Institutional Stem Cell Initiative for ongoing support.”

 A novel approach

So, this new finding sets forth the innovative concept that blood vessels are not just passive conduits for delivery of oxygen and nutrients, but are also programmed to maintain and proliferate stem cells and their mature forms in adult organs. Using a novel approach to harness the potential of endothelial cells by “co-culturing” them with stem cells, the researchers discovered the means to manufacture an unlimited supply of blood-related stem cells that may eventually ensure that anyone who needs a bone marrow transplant can get one. An article detailing these findings appears in the journal Cell Stem Cell.
“This study will have a major impact on the treatment of any blood-related disorder that requires a stem cell transplant,” says the study’s senior author. Currently, stem cells derived from bone marrow or umbilical cord blood are used to treat patients who require bone marrow transplants. Most stem cell transplants are successful, but because of the shortage of genetically matched bone marrow and umbilical cord blood cells, many patients cannot benefit from the procedure.

“Over the last few decades, substantial funding has been spent to develop platforms to expand adult stem cell cultures, but these efforts have never been able to coax an authentic adult stem cell to self-renew beyond a few days,” continues Dr. Rafii. “Most stem cells, even in the presence of multiple growth factors, serum, and support from generic non-endothelial stromal cells, die after a few days. However, employing our endothelial stem cell co-cultures, we can propagate bona fide adult stem cells in the absence of external factors and serum beyond 21 days with an expansion index of more than 400-fold.”

Endothelial Cells Could Generate Stem Cells

“However, we are the first group to demonstrate that endothelial cells elaborate a repertoire of stem-cell-active growth factors that not only stimulate stem cell expansion but also orchestrate differentiation of these stem cells into their mature progeny,” says Dr. Jason Butler, a senior investigator at Weill Cornell Medical College and first author of the study.

“So, for example, we have found that expression of specific stem-cell-active factors; namely Notch-ligands, by the endothelial cells lining the wall of working blood vessels; promote proliferation of the blood-forming stem cells. So, inhibition of these specific factors on the endothelial cells; resulted in the failure of the regeneration of the blood-forming stem cells. However, these findings suggest that endothelial cells directly; through expression of stem-cell-active cytokines, promote stem cell reconstitution.”

Human vascular cells induce the formation of organs

Dr. Rosenwaks says, “Generation of endothelial cells derived from diseased embryonic stem cells; that have propagation in our Derivation Unit will open up new avenues of research; to molecularly eavesdrop on the communication between vascular cells and stem cells. So, this innovative line of investigation; to determine how normal and abnormal human vascular cells induce the formation of organs during development of embryos; and how dysfunction of endothelial cells results in developmental defects; will lay the foundation for novel platforms for therapeutic organ regeneration.”

“Identification of as yet unrecognized growth factors produced; by human embryonic cell-derived endothelium and adult endothelial cells; that support stem cell expansion and differentiation will establish a new arena; in stem cell biology. So, we will be able to selectively activate endothelial cells not only to induce organ regeneration; but also to inhibit specifically the production of endothelial cell-derived factors in order to block the growth of tumors. However, our findings are the first steps; toward such goals and they highlight the potential of vascular cells; for generating sufficient stem cells for therapeutic organ regeneration, tumor targeting, and gene therapy applications;” concludes Dr. Rafii.