Regulatory Landscapes of Muscle Satellite Cells: From Mechanism to Application

Abstract

Muscle satellite cells (SCs), also known as muscle stem cells, are crucial for the regeneration, maintenance, and growth of skeletal muscles. SCs possess a distinctive capability to self-renew and differentiate, rendering them highly promising candidates for regenerative therapies and emerging cellular agriculture applications, including cultured meat production. This review explores the mechanisms that govern SC activation, proliferation, and commitment, and emphasizes their functional heterogeneity across anatomical regions. Region-specific gene expression, including that of homeobox (Hox) genes, contributes to the positional identity and myogenic potential. Understanding these regulatory landscapes is essential for optimizing SC expansion and improving their applications in muscle repair, stem cell-based therapies, and cellular manufacturing systems.

Keywords: Cell self renewal; Muscle development; Satellite cell; Skeletal muscle.

Fig. 1

Representative images of the satellite cell (SC) niche. SCs are located on the periphery of the muscle fiber. The positioning of the SCs between the sarcolemma and basal lamina is shown. SCs are surrounded by various cell types that can significantly influence their characteristics. These include endothelial cells, mesenchymal stem cells, pericytes, and connective tissue cells.

Fig. 2

Myogenic lineages and gene expression. Quiescent satellite cells (SCs) express PAX7, whereas lack MYOD expression. Upon activation, these cells undergo active proliferation and begin to coexpress both PAX7 and MYOD. Upon proliferation, SCs have the potential to either undergo self-renewal or proceed toward differentiation, depending on MYF5 expression. The orange table presents genes that are expressed in SCs at each state, along with representative transcription factors.

Fig. 3

Asymmetric and symmetric stem cell division. Satellite cells can self-renew via two types of stem cell division. Asymmetric cell division along the apico-basal axis yields one daughter cell that is committed to differentiation, whereas the other is focused on self-renewal. Symmetric cell division along the planar axis results in the formation of two daughter cells that either undergo differentiation or maintain self-renewal.

Fig. 4

Patterning and molecular specification of epaxial and hypaxial muscles from the dermomyotome. (A) A schematic representation of the early somite, which is derived from the paraxial mesoderm, demonstrates its differentiation into the dermomyotome and sclerotome. The dermomyotome subsequently gives rise to epaxial (trunk) and hypaxial (limb) muscle precursors. Epaxial muscles develop adjacent to the neural tube, whereas hypaxial muscles contribute to the musculature of the limbs and body wall. (B) Molecular signal regulating of muscle lineage specification. Wnt1 and Wnt3 from the dorsal neural tube, along with BMP4 from the surface ectoderm, induce the formation of the dorsal dermomyotome and promote epaxial muscle development. In contrast, Wnt7 promotes the formation of hypaxial muscles without BMP4, a condition maintained by Noggin, which is secreted by the notochord and floor plate and functions as a BMP4 antagonist.