Getting Stem Cells to Engraft More Effectively – With A Little Help From My “Friends”

The old Beatles song, “With A Little Help from My Friends” begins:

What would you think if I sang out of tune
Would you stand up and walk out on me?
Lend me your ears and I’ll sing you a song
And I’ll try not to sing out of key
Oh I get by with a little help from my friends
Mm I get high with a little help from my friends
Mm going to try with a little help from my friends

For mesenchymal stem cells, a little help from circulating stem cells, that is, their “friends” can make all the difference.

Ruei-Zeng Lin, in the laboratory of Juan M. Melero-Martin at the Boston Children’s Hospital and Department of Surgery at Harvard Medical School, in Boston, Massachusetts, have made a profound discovery that was published in the Proceedings of the National Academy of Sciences USA. They have shown that cells called “endothelial colony-forming cells” or ECFCs that not only circulate throughout the bloodstream but also contribute to the formation of new blood vessels, can function as “nurse cells” that positively regulate the regenerative potential of human mesenchymal stem cells.

Mesenchymal stem cells (MSCs) secrete a whole cocktail of healing molecules, but these cells also respond to several different molecules made by other cells, and ECFCs make some of these pro-MSC molecules.

In their experiment, Lin and others injected human MSCs isolated from white fat and bone marrow aspirates underneath the skin of immunodeficient mice in the presence or absence of ECFCs derived from human umbilical cord blood. The results were quite telling.

The engraftment of the MSCs (engraftment means the ability of the implanted stem cells to survive, differentiate and integrate into existing tissues) was regulated by a protein secreted by ECFCs called “platelet-derived growth factor BB” or PDGF-BB. When MSCs and ECFCs were transplanted together, the ECFCs significantly enhanced MSC engraftment. The MSCs not only survived better, showed much less cell death, but they also preserved the stem cell-character of the MSCs. THis is was established by the fact that when the implanted MSCs were removed and reimplanted into another mouse, these cells could repopulate secondary grafts. However, if MSCs were implanted without ECFCs, MSC engraftment was negligible. Also, if a drug called Tyrphostin AG1296 was used, MSCs engraftment was also negligible. Tyrphostin AG1296 inhibits the receptor for PDGF-BB and completely abrogates any EFCF-related enhancement of MSC function.  This shows that the enhancement of MSC engraftment by ECFCs is largely dependent on PDGF-BB-mediated signaling.

Strangely, transplanted MSCs that had been co-transplanted with ECFCs displayed fate-restricted differentiation in animals.  This simply means that the fat-based stem cells differentiated into fat and the bone marrow-derived MSCs differentiated into bone.  It seems that with the increased growth and stem cell function comes a more restricted differentiation program as well.  This could potentially prevent the phenomenon of “out-of-place” differentiation also known as heterotypic differentiation, which can cause the formation things like bone during fat transplantation or other such things.

These experiments show that blood-derived ECFCs can amplify the regenerative potential of MSCs via PDGF-BB – based signaling.  These data also suggest that the systematic use of ECFCs can improve MSC transplantation, and provides new insights into the therapeutic capabilities of ECFCs.  The authors add: “We foresee the use of ECFCs as a means to improve the outcome of MSC transplantation.”

This is a remarkable preclinical trial, but before it can work in humans, it must prove its efficacy and safety in human clinical trials and in other preclinical trials as well.