Towards stem cell therapies for skeletal muscle repair

Abstract

Skeletal muscle is an ideal target for cell therapy. The use of its potent stem cell population in the form of autologous intramuscular transplantation represents a tantalizing strategy to slow the progression of congenital muscle diseases (such as Duchenne Muscular Dystrophy) or regenerate injured tissue following trauma. The syncytial nature of skeletal muscle uniquely permits the engraftment of stem/progenitor cells to contribute to new myonuclei and restore the expression of genes mutated in myopathies. Historically however, the implementation of this approach has been significantly limited by the inability to expand undifferentiated muscle stem cells (MuSCs) in culture whilst maintaining transplantation potential. This is crucial, as MuSC expansion and/or genetic manipulation is likely necessary for therapeutic applications. In this article, we review recent studies that have provided a number of important breakthroughs to tackle this problem. Progress towards this goal has been achieved by exploiting biochemical, biophysical and developmental paradigms to construct innovative in vitro strategies that are guiding stem cell therapies for muscle repair towards the clinic.

The Future of Regenerative Medicine: Cell Therapy Using Pluripotent Stem Cells and Acellular Therapies Based on Extracellular Vesicles

“…Muscle regeneration involves the activation of PAX7 positive quiescent satellite cells that respond to tissue injury by proliferation and differentiation to give rise to MyoD positive progenitors called myoblasts (MBs) [ 98 ]. MBs then differentiate and fuse with myofibers to regenerate the damaged muscle [ 99 ].…”

“…Protocols have been described allowing the conversion of hPSCs into myoblasts through cytokines or small molecules exposition, recapitulating in vivo developmental cues [ 98 , 99 ]. Briefly, hPSCs are induced to presomitic mesoderm progenitors after activation of WNT and inhibition BMP signaling [ 99 , 105 ].…”

Long-term high-yield skeletal muscle stem cell expansion through staged perturbation of cytokine signaling in a soft hydrogel culture platform

“…MuSCs autologous or allogeneic cell therapies for systemic muscle wasting disorders or volumetric muscle loss (Judson and Rossi, 2020). Though protocols for FACS-based cell isolation have been refined, the scarcity of MuSCs in vivo (only ~2-5% of all skeletal muscle cells) relative to the number of MuSCs needed for transplantation therapies necessitates a robust expansion for clinical applications.…”

“…Recently, various culturing approaches have been utilized to stimulate ex vivo expansion of MuSCs in short-or intermediate-term cultures. Many small molecule and protein ligand factors have been shown to promote the expansion of adult mouse MuSCs, generally increasing functional Pax7-expressing cells ~2-15-fold in short-term (~1 wk) cultures (Almada and Wagers, 2016;Judson and Rossi, 2020). These approaches typically stimulate pathways promoting self-renewal or inhibit pathways driving myogenic differentiation.…”

“…Given their essential role in muscle regeneration, endogenous MuSCs and their culture progeny, a population of myogenic progenitors known as myoblasts, have been tested as a candidate for cellbased therapy for chronic muscle disease and wasting disorders, with limited clinical success (Almada and Wagers, 2016;Judson and Rossi, 2020). Notably, early-stage clinical trials using myoblasts demonstrated limited success in improving long-term muscle function to Duchenne muscular dystrophy patients, even though they resulted in detectable restoration of donor cell-derived dystrophin protein expression (Gussoni et al, 1992(Gussoni et al, , 1997.…”