Cellular interactions and microenvironment dynamics in skeletal muscle regeneration and disease

Abstract

Skeletal muscle regeneration relies on the intricate interplay of various cell populations within the muscle niche-an environment crucial for regulating the behavior of muscle stem cells (MuSCs) and ensuring postnatal tissue maintenance and regeneration. This review delves into the dynamic interactions among key players of this process, including MuSCs, macrophages (MPs), fibro-adipogenic progenitors (FAPs), endothelial cells (ECs), and pericytes (PCs), each assuming pivotal roles in orchestrating homeostasis and regeneration. Dysfunctions in these interactions can lead not only to pathological conditions but also exacerbate muscular dystrophies. The exploration of cellular and molecular crosstalk among these populations in both physiological and dystrophic conditions provides insights into the multifaceted communication networks governing muscle regeneration. Furthermore, this review discusses emerging strategies to modulate the muscle-regenerating niche, presenting a comprehensive overview of current understanding and innovative approaches.

Keywords: endothelial cells; fibro-adipogenic progenitors; macrophages; muscle niche dynamics; muscle stem cells; muscular dystrophies; regenerative medicine strategies; skeletal muscle regeneration.

FIGURE 1

Schematic representation of the cellular and molecular events involved in physiological skeletal muscle regeneration. Following injury, monocytes are recruited to the site of injury, differentiating into pro-inflammatory macrophages and induce a cascade of events. During the inflammatory phase, macrophages are in charge of phagocytosing cell debris and secrete pro-inflammatory cytokines, which induce muscle stem cells proliferation and the activation of endothelial cells and fibro-adipogenic progenitors (FAPs). The resolution of inflammation is triggered by the polarization of macrophages into anti-inflammatory/pro-regeneration phenotype. The secretion of growth factors and anti-inflammatory cytokines promote the differentiation of myogenic progenitors and the proliferation of FAPs and endothelial cells. During the restorative phase, the pericytes are recruited to support endothelial cells and allow the reestablishment of the vascular network, while FAPs undergo apoptosis and the Extracellular Matrix (ECM) is remodeled. This complex interplay ensures efficient muscle repair and functional recovery. Red lightning bolt indicates muscle injury. Created with BioRender.com.

FIGURE 2

Schematic representation of the crosstalk among key cellular players during physiological and pathological muscle regeneration. Muscle regeneration is mediated by the crosstalk between muscle cell populations such as muscle stem cells, macrophages (MPs), fibro-adipogenic progenitors (FAPs), endothelial cells, pericytes and their reciprocal cross talk. In physiological conditions, there is a tight balance of growth factors secreted by different muscle populations that orchestrate muscle regeneration allowing different processes such as controlled inflammation, MP polarization (MP switch), correct pericyte-endothelial cell interaction and FAPs function. However, during pathological muscle regeneration, this balance is disrupted leading to an altered crosstalk of the muscle cell populations. This leads to increased inflammation presenting MP intermediate states, uncontrolled Endothelial-to-Mesenchymal Transition, FAPs proliferation and differentiation into adipogenic or fibrogenic cells, resulting in altered ECM deposition and ultimately influencing disease exacerbation. Dashed arrows represent cell-to-cell communication. Solid arrows represent upregulated molecular factors in pathological conditions. Created with BioRender.com.