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.
Highlights
Our research group has isolated, by a modified preplate technique [1,2], a population of muscle-derived stem cells (MDSCs) from murine post-natal skeletal muscle
Stem cell therapy for articular cartilage repair we investigate the paracrine effect of stem cell therapy in the AC repair process of osteoarthritis (OA), where the cells used (MDSCs) have the ability to undergo chondrogenic differentiation but the paracrine effect of the donor cells on the promotion of angiogenesis is not required, but, needs to be inhibited
Stem cells injected into the site could aid and enhance the mediation of the repair process; knowing that the repair process relies primarily on host cell participation, it is easier to understand why BMP4-expressing MDSCs have a beneficial effect on both bone and AC repair since the repair process does not rely on the terminal differentiation of the donor cells per se
Summary
Our research group has isolated, by a modified preplate technique [1,2], a population of muscle-derived stem cells (MDSCs) from murine post-natal skeletal muscle. These reports support the hypothesis that the beneficial effect seen with MDSCs is likely due to the increased secretion of paracrine factors and not primarily due to the differentiation capacity of the donor cells toward a cardiac phenotype (for reviews refer to [28,75]), especially since the cardiac differentiation of these stem cells after implantation remains extremely low (Table 1).
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