Extracellular matrix: Brick and mortar in the skeletal muscle stem cell niche

Abstract

The extracellular matrix (ECM) is an interconnected macromolecular scaffold occupying the space between cells. Amongst other functions, the ECM provides structural support to tissues and serves as a microenvironmental niche that conveys regulatory signals to cells. Cell-matrix adhesions, which link the ECM to the cytoskeleton, are dynamic multi-protein complexes containing surface receptors and intracellular effectors that control various downstream pathways. In skeletal muscle, the most abundant tissue of the body, each individual muscle fiber and its associated muscle stem cells (MuSCs) are surrounded by a layer of ECM referred to as the basal lamina. The core scaffold of the basal lamina consists of self-assembling polymeric laminins and a network of collagens that tether proteoglycans, which provide lateral crosslinking, establish collateral associations with cell surface receptors, and serve as a sink and reservoir for growth factors. Skeletal muscle also contains the fibrillar collagenous interstitial ECM that plays an important role in determining tissue elasticity, connects the basal laminae to each other, and contains matrix secreting mesenchymal fibroblast-like cell types and blood vessels. During skeletal muscle regeneration fibroblast-like cell populations expand and contribute to the transitional fibronectin-rich regenerative matrix that instructs angiogenesis and MuSC function. Here, we provide a comprehensive overview of the role of the skeletal muscle ECM in health and disease and outline its role in orchestrating tissue regeneration and MuSC function.

Decoding Duchenne muscular dystrophy transcriptome to single nuclei level reveals clinical-genetic correlations

“…DMD-FAPs were characterized by an upregulation of the genes involved in expansion and remodelling of the ECM including but not limited to collagen and laminin genes (Col1a1, col6a6 and col3a1), metalloproteinases (Adamtsl1) and molecules involved in the assembly of the extracellular matrix (Sned1, Pcolce, Dcn). Interestingly, we observed significant differences in the expression of genes codifying ECM components between DMD and control samples, suggesting that there are differences not only in the quantity of some of the components but also in the composition of the matrix with a substantial increase in collagen I, III and VI which are part of the interstitial matrix, while collagen IV, one of the components of the basal lamina remained stable 57,58 . A complete understating of the impact that these changes have in muscle cells' behaviour is lacking, but it is know that ECM apart of providing structural support to cells, also facilitates communication, regulates cell growth, promotes or restrict cell movement and transmits mechanical signals 59 .…”

Cellular Dynamics of Skeletal Muscle Regeneration

“…Most previous research has used an ex-vivo system of SCs cultured on myofibers and based on the observation that the first division can be asymmetric, it has been proposed that early asymmetric division leads to early SC replenishment 11,59,60,63 . In addition, the inherent physical asymmetry of the SC niche 5,12,44 and observation of apical-basal divisions ex-vivo has led to the proposal that early apical-basal divisions generate asymmetric cell divisions that lead to SC replenishment 11,59,60 . However, our in vivo characterization and quantification of SC division angles found only planar cell divisions and no apical-basal divisions 1-2 DPI and agrees with the results of Webster and colleagues 52 .…”

“…During homeostasis, quiescent SCs occupy a distinct niche between the myofiber sarcolemma and the BM 5,12,44,45 . To visualize quiescent SCs in vivo, we imaged perfused fixed wholemount uninjured EDLs by confocal microscopy and reconstructed their three-dimensional structure with Fluorender (Fig.…”

“…a SC gives rise to two SCs) 12 . The niche within which quiescent SCs reside is inherently asymmetric, with the BM establishing the basal surface and the sarcolemma providing the apical surface 5,12,44 . Several studies 11,59,60 , based on cultured myofibers with attached SCs, have suggested that early asymmetric divisions are manifested as apical-basal cell division events, with the daughter cell adjacent to the BM becoming a quiescent SC, while the daughter adjacent to the sarcolemma differentiates into a MyoD+ myoblast.…”

Transcriptional Profiling of Skeletal Muscle Stem Cells After In Vivo Engraftment into a Heterologous Niche Environment

“…MuSCs are also affected by the myofibers with which they are associated (Lazure et al., 2020). Furthermore, fibroblasts (Mathew et al., 2011), T cells (Dumke & Lees, 2011), endothelial cells (Latroche et al., 2017), and pericytes (Kostallari et al., 2015) also populate the skeletal muscle, and they, along with the stiffness of the ECM (Schuler et al., 2022), also regulate MuSCs.…”