The emerging biology of muscle stem cells: implications for cell-based therapies

Abstract

Cell-based therapies for degenerative diseases of the musculature remain on the verge of feasibility. Myogenic cells are relatively abundant, accessible, and typically harbor significant proliferative potential ex vivo. However, their use for therapeutic intervention is limited due to several critical aspects of their complex biology. Recent insights based on mouse models have advanced our understanding of the molecular mechanisms controlling the function of myogenic progenitors significantly. Moreover, the discovery of atypical myogenic cell types with the ability to cross the blood-muscle barrier has opened exciting new therapeutic avenues. In this paper, we outline the major problems that are currently associated with the manipulation of myogenic cells and discuss promising strategies to overcome these obstacles.

Figure 1

Transplantation of genetically corrected cells requires engraftment into the satellite cell compartment. Since myogenic precursors fuse with damaged myofibers to form a single syncytium, establishing a genetically-corrected stem cell compartment will lead to the long-term replacement of diseased tissue. A: Cross-section through the TA muscle showing GFP+ satellite cells (arrows) and myofibers. A′: A GFP+ satellite cell is observed on a single GFP− myofiber. In this case, GFP+ satellite cells will participate in future remodeling of muscle tissue and incorporate genetic corrections into host myofibers making them GFP+ as well. A graft of committed progenitors rather leads to excessive differentiation and will marginally engraft into the stem cell compartment. B: GFP is only found in myofibers but not satellite cells. B′: Micrograph of a GFP+ myofiber which is derived from GFP+ satellite cells that differentiated. Note that all fiber associated cells are GFP−. Although the establishment of genetically-corrected myofibers is the ultimate goal, without a stem cell population, the effects of these transplants are likely to diminish due to tissue turnover. C: Cartoon schematic of the possible long-term transplantation outcomes described above.

Figure 2

Representation of the satellite cell niche. Satellite cells reside within a specialized microenvironment, tightly packed between the ECM and their host myofibers. Cell-cell vs. cell-matrix interactions polarize the satellite cell niche in an apical-basal orientation and play a role in the determination of cell fate in asymmetric divisions. Paracrine interactions with various other cell-types (immune cells, fibroblasts, endothelial cells, vessel-associated cells, and the host myofiber) also modulate satellite cell behavior during homeostasis and regeneration.