Abstract
SummarySatellite cells are adult muscle stem cells residing in a specialized niche that regulates their homeostasis. How niche-generated signals integrate to regulate gene expression in satellite cell-derived myoblasts is poorly understood. We undertook an unbiased approach to study the effect of the satellite cell niche on satellite cell-derived myoblast transcriptional regulation and identified the tumor suppressor p53 as a key player in the regulation of myoblast quiescence. After activation and proliferation, a subpopulation of myoblasts cultured in the presence of the niche upregulates p53 and fails to differentiate. When satellite cell self-renewal is modeled ex vivo in a reserve cell assay, myoblasts treated with Nutlin-3, which increases p53 levels in the cell, fail to differentiate and instead become quiescent. Since both these Nutlin-3 effects are rescued by small interfering RNA-mediated p53 knockdown, we conclude that a tight control of p53 levels in myoblasts regulates the balance between differentiation and return to quiescence.
Highlights
Satellite cells (SCs) are quiescent muscle stem cells residing in a specialized anatomical niche located between the plasma membrane of the muscle fiber and the surrounding basal lamina (Mashinchian et al, 2017)
Myogenin-positive (MYOG+) cells are occasionally observed on the third day in culture (Figure 1B), suggesting that SCderived myoblasts in dispersed cultures begin to exit the cell cycle and undergo terminal differentiation between 48 and 72 hr after isolation
On day 3 in culture, MYOG+ cells are observed amongst myofiber-associated myoblasts (Figures 1C and 1D), which are cultured in the same medium as dispersed myoblasts
Summary
Satellite cells (SCs) are quiescent muscle stem cells residing in a specialized anatomical niche located between the plasma membrane of the muscle fiber and the surrounding basal lamina (Mashinchian et al, 2017). After one or more rounds of proliferation, the vast majority of SC-derived muscle progenitors (called myoblasts) exit the cell cycle and enter a terminal G0 phase that leads to differentiation, followed by fusion to existing damaged muscle fibers to repair them or one-another to generate new muscle fibers. In a second model, proliferating myoblasts are induced to overexpress Pax, which in turn inhibits myogenin expression and promotes entry into a mitotically quiescent state (Olguın and Olwin, 2004; Wen et al, 2012) In both cases, a key role appears to be played by the extracellular environment, called the SC niche (Mashinchian et al, 2017)
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