Muscle Stem Cell Mechanical Memory study Published in PNAS

Skeletal muscle stem cells (MuSCs) are essential for muscle maintenance and repair throughout life. MuSCs reside in a niche situated between muscle fibers and the surrounding basal lamina extracellular matrix (ECM). This niche provides critical signals that regulate MuSC activation, differentiation, and quiescence. MuSCs are highly sensitive to both biochemical signals from ECM molecules like laminin and collagen, and to the biophysical properties of the ECM itself, particularly its stiffness. MuSCs perform best on substrates mimicking the stiffness of healthy muscle (~12 kPa). Stiffer substrates can impair their regenerative potential. Aging and diseases like Duchenne Muscular Dystrophy increase ECM stiffness, which negatively affects MuSC function. Therefore, understanding MuSC responses to ECM stiffness is crucial for developing therapies to improve muscle regeneration.

In laboratory studies, myoblasts (derived from MuSCs) generally show enhanced proliferation on stiffer surfaces, unlike freshly isolated MuSCs that expand better on softer substrates. This difference is thought to arise due to cell state- MuSCs are initially quiescent and only enter the cell cycle after a few days in culture, whereas myoblasts are already proliferating.

In a study recently published in PNAS designed to explore the idea of "mechanical memory"—where past mechanical environments influence future cell behavior— Chris Madl and co-authors used advanced hydrogel platforms with light-sensitive properties to control substrate stiffness to study MuSC responses. The team's findings indicate that while brief exposure to stiff substrates does not affect MuSC expansion, prolonged exposure leads to reduced expansion and premature differentiation or dysfunctional quiescence. Conversely, a short period on soft substrates or inhibition of specific signaling pathways can preserve MuSC expansion potential, even through later exposed to stiffer conditions. These insights, supported by single-cell RNA sequencing, offer potential therapeutic targets to enhance MuSC function in aging and disease, and highlight the value of dynamic hydrogel systems in studying mechanosensitivity.