Transcriptional reprogramming of skeletal muscle stem cells by the niche environment

Abstract

Adult stem cells are indispensable for tissue regeneration, but their function declines with age. The niche environment in which the stem cells reside plays a critical role in their function. However, quantification of the niche effect on stem cell function is lacking. Using muscle stem cells (MuSC) as a model, we show that aging leads to a significant transcriptomic shift in their subpopulations accompanied by locus-specific gain and loss of chromatin accessibility and DNA methylation. By combining in vivo MuSC transplantation and computational methods, we show that the expression of approximately half of all age-altered genes in MuSCs from aged male mice can be restored by exposure to a young niche environment. While there is a correlation between gene reversibility and epigenetic alterations, restoration of gene expression occurs primarily at the level of transcription. The stem cell niche environment therefore represents an important therapeutic target to enhance tissue regeneration in aging.

Aging impairs skeletal muscle regeneration by promoting fibro/fatty degeneration and inhibiting inflammation resolution via fibro-adipogenic progenitors

“…Previous reports have described a reduction of FAPs in uninjured muscle during aging 10,24 . Upon injury the situation could depend on the specifics of the experimental layout, physiological status and age, as age-related failure of FAPs to expand has been reported 10 , while our own observations suggest enhanced FAP expansion, which align with scRNA-seq and tissue-array data at steady-state in old muscle 8,68 .…”

“…MuSCs also interact with their local microenvironment, the muscle stem cell niche. These interactions play a critical role in regulating MuSCs behavior and affect the outcome of regeneration, which in the context of aging has been linked to fibro/fatty degeneration of muscle tissue 4,[9][10][11] .…”

Derepression of transposable elements enhances interferon beta signaling and stem/progenitor cell activity after proton irradiation

“…Radiation-induced loss of genomic integrity and subsequent changes in its microenvironment can profoundly affect the self-renewal capacity and longevity of stem cells 7,33,34 . Given the stronger IFN-β response and self-renewal capacity observed upon proton irradiation, we explored whether IFN-β signaling in the irradiated stem/progenitor cell microenvironment affects self-renewal potential.…”

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

“…FAPs will display an altered transcriptome, initially expressing chemokines to attract immune cells, and will also express increased levels of ECM proteins, indicating that they are remodeling the muscle niche (de Micheli et al, 2020). Aging is another condition in which the niche will be heavily altered, we see a change in the macrophage population and the number of FAPs is increased (Lazure et al, 2023). This provides a major challenge in the efforts to uncouple the effects of aging on MuSC function from the effect of the changing niche as the two are inextricably linked.…”

“…The RNA‐seq data utilized in this protocol was retrieved from GSE171998 (Lazure et al., 2023). Other tools and materials (or their source) that support the protocol are available from the corresponding author upon request.…”