Introduction

It has been known for more than a century that skeletal muscle, the most abundant tissue of the body, has the ability to regenerate new muscle fibers after it has been damaged by injury or as a consequence of diseases such as muscular dystrophy (1). Muscle fibers are syncytial cells that contain several hundred nuclei within a continuous cytoplasm. Therefore, whether the process of regeneration depends upon the fusion of mononucleated precursor cells or upon the fragmentation of dying muscle fibers, which release new cells, remained controversial for a long time, even after the demonstration by Beatrice Mintz and Wilber Baker (2) that multinucleated fibers are formed by the fusion of single cells. In 1961, Alexander Mauro (3) observed mononuclear cells between the basal lamina that surrounds each muscle fiber and the plasma membrane of the muscle fiber and named them satellite cells (SCs) (Figure ​(Figure1).1). SCs were later accepted to be, and are still considered today, the main players in skeletal muscle regeneration. SCs also contribute to the postnatal growth of muscle fibers, which in adults contain approximately 6–8 times more nuclei than in neonates, all of them being irreversibly postmitotic.

Figure 1

Asymmetric cell division during activation of SCs.

In addition to SCs, other progenitors located outside the basal lamina, including pericytes, endothelial cells, and interstitial cells, have been shown to have some myogenic potential in vitro or after transplantation. The developmental origin of these progenitors is unclear, as is their lineage relationship with SCs, even though they may feed, to some extent, into the SC compartment (4).

There is much interest in understanding the cellular and molecular mechanisms underlying skeletal muscle regeneration in different contexts because such knowledge might help in the development of cell therapies for diseases characterized by skeletal muscle degeneration. These diseases include muscular dystrophy, the term for a group of inherited disorders characterized by progressive muscle wasting and weakness leading to a variable degree of mobility limitation, including confinement to a wheelchair and, in the most severe forms, heart and/or respiratory failure (5). Many muscular dystrophies arise from loss-of-function mutations in genes encoding cytoskeletal and membrane proteins, the most common and severe being Duchenne muscular dystrophy (DMD), which is caused by mutations in the gene encoding dystrophin, an integral part of a complex that links the intracellular cytoskeleton with the extracellular matrix in muscle. Muscular dystrophies are some of the most difficult diseases to treat, as skeletal muscle is composed of large multinucleated fibers whose nuclei cannot divide. Consequently, cell therapy has to restore proper gene expression in hundreds of millions of postmitotic nuclei (6).

In this Review, we discuss recent work indicating the possible existence of a stem/progenitor cell compartment in adult muscle (see also ref. 7) as well as studies related to the derivation of myogenic cells from embryonic and induced pluripotent stem cells (PSCs) for the development of new cell therapy strategies for diseases of skeletal muscle. An overview of clinical trials based upon transplantation of skeletal muscle stem cells is also provided. Neither the role of SCs in aging skeletal muscle nor the SC niche are discussed here due to space constraints, and readers are directed to excellent recent reviews on these topics by Suchitra Gopinath and Thomas Rando (8) and Michael Rudnicki and colleagues (9), respectively.

SCs