Morphological, molecular, and electrophysiological aspects of skeletal muscle satellite cell-niche interactions: Focus on interstitial stromal non-myogenic cells

Satellite cells (SCs) are recognized as the resident stem cells of adult skeletal muscles, essential for post-natal skeletal muscle growth and regeneration following focal myotrauma. In healthy muscle SCs are quiescent but in response to damage or growth signals, they become activated to proliferate and differentiate to form new myofibers. A small population self-renews for replenishing the basal pool for future demands. The ability of SCs to precisely balance quiescence, self-renewal, and myogenic commitment/differentiation is essential for ensuring long-term muscle homeostasis and tissue maintenance. Their state and functionality are strictly regulated by different intrinsic and extrinsic cues, the latter deriving from the microenvironment SC reside, known as the niche. The niche is a dynamic compartment where extracellular matrix components, soluble factors, mechanical stimuli and multiple interacting cell populations modulate morphological, molecular and electrophysiological properties of SCs. This review provides an updated overview of the morpho-functional features of SCs and of non-myogenic stromal interstitial cells, highlighting their reciprocal crosstalk within the regenerative niche. Such stromal cells play a dual role acting as “good” or “bad” cells: while functioning as nursing cells for SCs during muscle repair/regeneration via juxtacrine and paracrine interactions, their excessive accumulation and adoption of fibrotic/fat phenotype may lead to an aberrant tissue repair, compromising muscle function. A deeper understanding of SC biology and of the collaborative spatiotemporal cell interactions in the healthy, damaged and regenerative niche is essential to identify potential novel targets and to better address intervention for maintaining, restoring or enhancing muscle regeneration capacity and mitigating the deleterious effects of extended, severe or pathological muscle damage.