Terminal differentiation is not a major determinant for the success of stem cell therapy - cross-talk between muscle-derived stem cells and host cells

Abstract

We have found that when muscle-derived stem cells (MDSCs) are implanted into a variety of tissues only a small fraction of the donor cells can be found within the regenerated tissues and the vast majority of cells are host derived. This observation has also been documented by other investigators using a variety of different stem cell types. It is speculated that the transplanted stem cells release factors that modulate repair indirectly by mobilizing the host's cells and attracting them to the injury site in a paracrine manner. This process is loosely called a 'paracrine mechanism', but its effects are not necessarily restricted to the injury site. In support of this speculation, it has been reported that increasing angiogenesis leads to an improvement of cardiac function, while inhibiting angiogenesis reduces the regeneration capacity of the stem cells in the injured vascularized tissues. This observation supports the finding that most of the cells that contribute to the repair process are indeed chemo-attracted to the injury site, potentially through host neo-angiogenesis. Since it has recently been observed that cells residing within the walls of blood vessels (endothelial cells and pericytes) appear to represent an origin for post-natal stem cells, it is tempting to hypothesize that the promotion of tissue repair, via neo-angiogenesis, involves these blood vessel-derived stem cells. For non-vascularized tissues, such as articular cartilage, the regenerative property of the injected stem cells still promotes a paracrine, or bystander, effect, which involves the resident cells found within the injured microenvironment, albeit not through the promotion of angiogenesis. In this paper, we review the current knowledge of post-natal stem cell therapy and demonstrate the influence that implanted stem cells have on the tissue regeneration and repair process. We argue that the terminal differentiation capacity of implanted stem cells is not the major determinant of the cells regenerative potential and that the paracrine effect imparted by the transplanted cells plays a greater role in the regeneration process.

Human muscle–derived stem/progenitor cells promote functional murine peripheral nerve regeneration

“…Therefore, mechanisms that may contribute to the nerve healing observed here include the recruitment of host cells to the site of injury, proliferation, and differentiation of host cells toward a supporting cell lineage, such as Schwann cells, which release cytokines that exert neuroprotective effects independently of neurogenesis (59,60). Thus, our results suggest that the observed regeneration is, at least in part, mediated via a paracrine/endocrine mechanism(s), as previously discussed (61,62). In fact, our recent results demonstrate that young functional MDSPCs can restore the dysfunction of aged MDSPCs when cocultured and, when transplanted, are able to rescue the homeostasis of mice with accelerated aging through secreted factors that act systemically (49), suggesting that cultures' exogenous and lesions' endogenous factors likely determine the fate of donor stem cells.…”

Improving the Post-Stroke Therapeutic Potency of Mesenchymal Multipotent Stromal Cells by Cocultivation With Cortical Neurons: The Role of Crosstalk Between Cells

“…This is also applicable to the host cells, which can respond to the presence of alien cells by the synthesis of some biological compounds. This "crosstalk" between "roommate" cells or even remote organs within one organism has been suggested, and a large amount of data supporting this phenomenon has been published [35][36][37][38][39]. However, intercellular communication by excretion of some biologically active compounds for reception by neighboring cells is somewhat limited by diffusion.…”

Role of angiogenesis after muscle derived stem cell transplantation in injured medial collateral ligament

“…Finally, as previously described in other models of tissue repair, these results indicate that MCL repair after stem cell therapy occurs due to a paracrine effect elicited by the cells that involves angiogenesis since blocking VEGF significantly impaired MCL repair. 44 …”