| Reconstruction of the adult muscle tissue relies on stem cells situated in a niche between the basal lamina and sarcolemma, but the molecular mechanisms of cell fate decisions, especially self-renewal, during muscle regeneration remains unclear. We report that the local extracellular matrix surrounding the muscle stem cell in healthy, uninjured tissue is permissive for planar and apical-basal division orientations that lead to either symmetric or asymmetric cell fates, but that the increased extracellular matrix deposition during injury physically alters the niche architecture to significantly favour symmetric divisions in the planar orientation. We demonstrate that the addition of soluble ligands such as Wnt7a leads to a significant increase of self-renewal divisions instead of differentiation, but only when coupled with 3D culture in a stiff environment. Together, these results suggest that biophysical cues such as niche stiffness work synergistically with biochemical cues like Wnt7a signaling to regulate muscle stem cell self-renewal. |
