Infoscience

Thesis

Novel interventions to recover the regenerative capacity of aged skeletal muscle by targeting the interactions in the stem cell niche

The remarkable ability of skeletal muscle to regenerate upon injury is conferred by tissue-resident stem cells called satellite cells. With age, the regenerative capacity of muscle stem cells (MuSCs) dramatically declines. Developing strategies to enhance muscle repair in elderly people is therefore required; in particular to accelerate their recovery from injuries following falls or from surgical interventions affecting muscle tissues. As the causes of MuSC dysfunction with age are multi-systemic, we decided to dissect age-related changes at different levels of the MuSC environment, in order to uncover synergistic ways to restore their regenerative capacities. This thesis describes three major interventions at the extracellular matrix, cell-cell interaction and tissue/systemic level that successfully restored skeletal muscle regeneration in aged mice. Using a proteomic screen, we identified fibronectin as a structural and signaling molecule of the extracellular matrix that is lost in the aged muscle niche. Loss of fibronectin in aged regenerating muscle primarily arises from perturbed cellular turnover of hematopoietic and endothelial cells which were shown to be the major fibronectin producers in muscle upon injury. Our work also uncovered that the function of old MuSCs is impaired by loss of adhesion and cell death by anoikis, and can be rescued by fibronectin treatment both ex vivo and in vivo. At the molecular level, loss of fibronectin is an upstream trigger leading to perturbed MuSC signaling. Fibronectin treatment rescues perturbations of pathways, such as p38 and ERK, that were previously known to be altered in aged MuSCs, as well as the newly discovered age-related perturbations of FAK signaling. Altogether we demonstrated that aging impairs the remodeling of the extracellular matrix of the MuSC niche, and thereby triggers multiple dysfunction of old MuSCs that can be rescued therapeutically. In a second project, we dissected the cellular cross-talk between MuSCs and non-myogenic support cells called Fibro-Adipogenic Progenitors (FAPs). We uncovered that the adipogenic fate of FAPs is tightly correlated to the muscle micro-environment and the myogenic regenerative capacity in different models of regeneration and aging. The function of FAPs and their cross-talk with MuSCs are impaired with age. We identified the secreted protein WISP1 as a paracrine communication factor between FAPs and MuSCs which is perturbed with age. Treating aged mice with WISP1 restored stem cell function and muscle regeneration, highlighting the possibility to target the cross-talk of MuSC with other cells of the niche to ameliorate their function. Our last project identified altered signaling of the small circulating peptide apelin in aged MuSCs through lowered circulating levels of apelin and down-regulation of its receptor APJ in aged MuSCs. We demonstrated that apelin treatment rescued muscle stem cell function and regeneration in aged mice, highlighting that MuSC dysfunction can also be targeted systemically. Taken together, these approaches reveal the multiple possibilities to ameliorate muscle repair by targeting MuSC interactions with their niche. Our results also pave the way to develop integrated therapeutic strategies to boost old MuSC function.

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