Roles of nonmyogenic mesenchymal progenitors in pathogenesis and regeneration of skeletal muscle

Abstract

Adult skeletal muscle possesses a remarkable regenerative ability that is dependent on satellite cells. However, skeletal muscle is replaced by fatty and fibrous connective tissue in several pathological conditions. Fatty and fibrous connective tissue becomes a major cause of muscle weakness and leads to further impairment of muscle function. Because the occurrence of fatty and fibrous connective tissue is usually associated with severe destruction of muscle, the idea that dysregulation of the fate switch in satellite cells may underlie this pathological change has emerged. However, recent studies identified nonmyogenic mesenchymal progenitors in skeletal muscle and revealed that fatty and fibrous connective tissue originates from these progenitors. Later, these progenitors were also demonstrated to be the major contributor to heterotopic ossification in skeletal muscle. Because nonmyogenic mesenchymal progenitors represent a distinct cell population from satellite cells, targeting these progenitors could be an ideal therapeutic strategy that specifically prevents pathological changes of skeletal muscle, while preserving satellite cell-dependent regeneration. In addition to their roles in pathogenesis of skeletal muscle, nonmyogenic mesenchymal progenitors may play a vital role in muscle regeneration by regulating satellite cell behavior. Conversely, muscle cells appear to regulate behavior of nonmyogenic mesenchymal progenitors. Thus, these cells regulate each other reciprocally and a proper balance between them is a key determinant of muscle integrity. Furthermore, nonmyogenic mesenchymal progenitors have been shown to maintain muscle mass in a steady homeostatic condition. Understanding the nature of nonmyogenic mesenchymal progenitors will provide valuable insight into the pathophysiology of skeletal muscle. In this review, we focus on nonmyogenic mesenchymal progenitors and discuss their roles in muscle pathogenesis, regeneration, and homeostasis.

Keywords: PDGFRα; adipogenesis; fibrosis; heterotopic ossification; mesenchymal progenitors; muscle atrophy; muscle regeneration; satellite cells.

Figure 1

Localization of PDGFRα⁺ mesenchymal progenitors in normal muscle. (A) Fresh frozen section of mouse TA muscle subjected to immunofluorescence staining for M-cadherin (M-cad), PDGFRα, and laminin α2, and subsequently to HE staining. Arrows indicate PDGFRα⁺ mesenchymal progenitors and arrowhead indicates satellite cells. Scale bar: 10 μm. (B) Schematic view of (A). Mesenchymal progenitors that reside in muscle interstitium express collagen VI, follistatin, and laminin α2, and maintain muscle mass in a normal physiological condition.

Figure 2

The behavior of PDGFRα⁺ mesenchymal progenitors in dystrophic muscle. Fresh frozen section of mdx diaphragm subjected to immunofluorescence staining for laminin α2, PDGFRα, and collagen I, and subsequently to HE staining. Scale bar: 20 μm.

Figure 3

Localization of PDGFRα⁺ mesenchymal progenitors in regenerating muscle. (A) Fresh frozen section of regenerating muscle subjected to immunofluorescence staining for M-cadherin (M-cad), PDGFRα, and laminin α2, and subsequently to HE staining. Scale bar: 10 μm. (B) Schematic view of (A). Mesenchymal progenitors encircle the sheath of basement membrane in which satellite cells undergo active myogenesis. Mesenchymal progenitors stimulate satellite cell expansion and promote satellite cell-dependent myogenesis. Factors responsible for these effects remain to be identified.