



When they were discovered, mesenchymal stem cells seemed ready to get in the swim of regenerative medicine. But they floundered. In hundreds of clinical trials, stem cells sank long before they could help patients.

Mesenchymal stem cells, which are found in bone marrow and can give rise to bone, fat, and muscle tissue, seem to do well enough in culture—a fact that led researchers from the Harvard Stem Cell Institute (HSCI) to wonder if the laboratory dish was serving as a kind of kiddy pool. Maybe all the attempts to put mesenchymal stem cells into the body amounted to having them dive into the deep end, sink-or-swim style.

Observant as any lifeguard, Juan Melero-Martin, Ph.D., an HSCI affiliated faculty member and an assistant professor of surgery at Boston Children's Hospital, Harvard Medical School, proclaimed, “We are losing mesenchymal stem cells very rapidly when we transplant them into the body in part because we are not giving them what they need.”

It turned out that what mesenchymal stem cells needed were buddies: endothelial colony-forming cells (ECFCs). ECFCs, it was well known, circulate in peripheral blood and promote blood vessel formation. Less certain, however, was the ability of ECFCs to stimulate stem cells in vivo, enhancing their survival by means of encouraging signals.

To explore the possibility that ECFCs could assist mesenchymal stem cells by functioning as paracrine mediators, Dr. Melero-Martin and his colleagues transplanted both cell types together. Co-transplantation kept the mesenchymal stem cells alive longer in mice after engraftment, up to a few weeks compared to hours without co-transplantation. This improved survival gave the mesenchymal stem cells sufficient time to display their full regenerative potential, generating new bone or fat tissue in the recipient mouse body.

The researcher’s findings appeared June 30 in the Proceedings of the National Academy of Sciences, in an article entitled “Human endothelial colony-forming cells serve as trophic mediators for mesenchymal stem cell engraftment via paracrine signaling.” The article indicated that mesenchymal stem cell engraftment “was regulated by ECFC-derived paracrine factors via platelet-derived growth factor BB (PDGF-BB)/platelet-derived growth factor receptor (PDGFR)-β signaling. Co-transplanting ECFCs significantly enhanced MSC engraftment by reducing early apoptosis and preserving stemness-related properties of PDGFR-β+ MSCs, including the ability to repopulate secondary grafts.”

In other words, early angiocrine support ultimately enables extensive engraftment and long-term differentiation of transplanted mesenchymal stem cells.

“In the body, these cells sit very close to the capillaries, constantly receiving signals from them, and even though this communication is broken when we isolate mesenchymal stem cells in a laboratory dish, they seem to be ok because we have learned how to feed them,” explained Dr. Melero-Martin. “But when you put the mesenchymal stem cells back into the body, there is a period of time when they will not have this proximity to capillary cells and they start to die; so including these blood vessel-forming cells from the very beginning of a transplantation made a major difference.”

Dr. Melero-Martin’s research has immediate translational implications, as current mesenchymal clinical trials don’t follow a co-transplantation procedure. He is already collaborating with surgical colleagues at Boston Children’s Hospital to see if his discovery can help improve fat and bone grafts. However, giving patients two different types of cells, as opposed to just one, would require more time and experiments to determine safety and efficacy. Melero-Martin is seeking to identify the specific signals mesenchymal stem cells receive from the blood vessel-forming cells in order to be able to mimic the signals without the cells themselves.



























