Transcriptional Reprogramming of Skeletal Muscle Stem Cells by the Niche Environment

Abstract

Adult stem cells are indispensable for tissue regeneration. Tissue-specific stem cells reside in a specialized location called their niche, where they are in constant cross talk with neighboring niche cells and circulatory signals from their environment. Aging has a detrimental effect on the number and the regenerative function of various stem cells. However, whether the loss of stem cell function is a cause or consequence of their aging niche is unclear. Using skeletal muscle stem cells (MuSCs) as a model, we decouple cell-intrinsic from niche-mediated extrinsic effects of aging on their transcriptome. By combining in vivo MuSC heterochronic transplantation models and computational methods, we show that on a genome-wide scale, age-related altered genes fall into two distinct categories regarding their response to the niche environment. Genes that are inelastic in their response to the niche exhibit altered chromatin accessibility and are associated with differentially methylated regions (DMRs) between young and aged cells. On the other hand, genes that are restorable by niche exposure exhibit altered transcriptome but show no change in chromatin accessibility or DMRs. Taken together, our data suggest that the niche environment plays a decisive role in controlling the transcriptional activity of MuSCs, and exposure to a young niche can reverse approximately half of all age-associated changes that are not epigenetically encoded. The muscle niche therefore serves as an important therapeutic venue to mitigate the negative consequence of aging on tissue regeneration.

The mini-IDLE 3D biomimetic culture assay enables interrogation of mechanisms governing muscle stem cell quiescence and niche repopulation

“…Interestingly, the myoblasts used to fabricate all of the muscle tissues for this study were derived from young mice, meaning that the aged MuSCs were exposed to a young niche. We cannot rule out the possibility that the young biomimetic muscle niche partially rescued aged MuSC function, as has been reported by others ( Conboy et al, 2005 ; Lazure et al, 2022 ). Indeed, we anticipate that aged MuSCs introduced to muscle tissues fabricated from myoblasts derived from aged donors and/or exposed to an aging systemic environment will induce further functional decline.…”

Rescue of aged muscle stem cell quiescence defects by AKT inhibition revealed with a 3D biomimetic culture assay

“…Interestingly, the myoblasts used to fabricate all of the muscle tissues for this study were derived from young mice, meaning that the aged MuSCs were exposed to a young niche. We cannot rule out the possibility that the young biomimetic muscle niche partially rescued aged MuSC function, as has been reported by others 71,72 . Indeed, we anticipate that aged MuSCs introduced to muscle tissues fabricated from myoblasts derived from aged donors and/or exposed to an aging systemic environment will induce further functional decline.…”

Decline of regenerative potential of old muscle stem cells: contribution to muscle aging

“…Studies culturing proliferating myoblasts in conditions resembling young and old niche stiffness have shown that increased stiffness in the aged niche is associated with a decrease in the proliferation of MuSCs and, thus, reducing their regenerative capabilities [156]. A recent study using single‐cell RNA‐seq of muscle resident FAPs from young and old mice has shown that the number of FAPs is increased in the old muscle [67]. This could lead to increased ECM deposition and tissue stiffness in the aged niche [67].…”

“…A recent study using single‐cell RNA‐seq of muscle resident FAPs from young and old mice has shown that the number of FAPs is increased in the old muscle [67]. This could lead to increased ECM deposition and tissue stiffness in the aged niche [67]. Accumulation of ECM and increased stiffness in aging leads to increased fibrosis which is associated with a decline in the function of MuSCs [150].…”

“…Similar to previous parabiosis studies [35], this recent study once again implies that the systemic environment plays a key role in the capacity for MuSC regeneration and is a critical factor involved in MuSC aging. To further elucidate the contribution of the niche on MuSC function at the genomic level, a recent study compared the gene expression profile of aged MuSCs before and after a 3‐week engraftment into a young niche [67]. Since nearly half of age‐altered genes were shown to have reversible expression in response to young niche exposure, this points to the niche being a direct regulator of the MuSC transcriptional profile and potentially their functional profile as well [67].…”