Muscle stem cells get a new look: Dynamic cellular projections as sensors of the stem cell niche

Abstract

Cellular mechanisms whereby quiescent stem cells sense tissue injury and transition to an activated state are largely unknown. Quiescent skeletal muscle stem cells (MuSCs, also called satellite cells) have elaborate, heterogeneous projections that rapidly retract in response to muscle injury. They may therefore act as direct sensors of their niche environment. Retraction is driven by a Rac‐to‐Rho GTPase activity switch that promotes downstream MuSC activation events. These and other observations lead to several hypotheses: (1) projections are morphologically dynamic at quiescence, providing a surveillance function for muscle damage; (2) quiescent projection dynamics are regulated by the relative balance of Rac and Rho activities promoted by niche‐derived cues; (3) projections, particularly their associated filopodia, sense tissue damage via changes to the biomechanical properties of the niche and/or detection of signaling cues released by damaged myofibers; and (4) the dynamic nature of projections results in a population of MuSCs with heterogeneous functional properties. These concepts may extend to other types of quiescent stem cells, as well as prove useful in translational research settings.

Cadherin-dependent adhesion is required for muscle stem cell niche anchorage and maintenance

“…Cadherin-catenin complexes are best understood as factors bridging cell-cell contact and adhesion with cytoskeletal structure and dynamic regulation of cell tension (Leckband & de Rooij, 2014; Mège & Ishiyama, 2017). Work on MuSC cellular projections suggests that the first step in injury-induced MuSC activation may be a change to the biomechanical environment of the niche (Krauss & Kann, 2023). Additionally, changes to the actin and microtubule cytoskeletons are among the earliest events visible after MuSC activation (Kann et al, 2022).…”

Imaging analysis for muscle stem cells and regeneration

“…Historically, MuSCs have been described as small, fusiform cells with a high nuclear-to-cytoplasmic ratio ( Kann et al, 2021 ; Krauss and Kann, 2023 ) ( Table 1 ). With improvements to imaging and muscle preparation techniques, studies have revealed that quiescent MuSCs are a heterogeneous population with cellular projections.…”

“…Today, the identification of quiescence-promoting factors has mainly come from loss-of-function experiments in which the loss of such factors led to an activated MuSC phenotype. The mechanisms by which these factors maintain MuSC quiescence and how their dynamics change during the Q-A transition have remained unclear until recently with the advent of imaging advancements ( Kann et al, 2021 ; Krauss and Kann, 2023 ). These recent advancements in imaging techniques have opened up new possibilities for studying MuSCs, instilling optimism in the field and stimulating further research into the field.…”

“…The skeletal muscle tissue itself contains a variety of the following different cell types: multinucleated muscle fibers (myofibers), muscle stem cells (also known as muscle satellite cells or MuSCs), endothelial cells (ECs), pericytes (PCs), side population (SP) cells, mesenchymal progenitors/fibro-adipogenic progenitors (FAPs), motor neurons, Schwann cells, muscle spindle cells for peripheral nerves, immune cells, and undefined fibroblastic cells ( Asakura et al, 2001 ; Asakura et al, 2002 ; Verma et al, 2018 ; Wosczyna et al, 2018 ; Cutler et al, 2022 ). The multinucleated myofibers are long-lived and elongated cells with little turnover without disease or injury ( Kann et al, 2021 ; Krauss and Kann, 2023 ). However, following injury, the skeletal muscle has the unique ability to regenerate.…”

“…Upon injury, MuSCs undergo an activation process in which they activate, proliferate, and differentiate to form new muscle fibers. In addition, MuSCs undergo a self-renewal process to replenish the resident stem cell pool, allowing the muscle to undergo the regeneration process for multiple injuries ( Kann et al, 2021 ; Krauss and Kann, 2023 ). Although several decades of research have gone into understanding the signaling factors and cellular interactions involved in the MuSC quiescence-to-activation transition (Q-A transition), the overall mechanism of this process still requires further exploration.…”