The Satellite Cell Niche Regulates the Balance between Myoblast Differentiation and Self-Renewal via p53

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.

Stem Cell Aging in Skeletal Muscle Regeneration and Disease

“…Increased expression of several cell cycle inhibitors, such as p53 [124,125], p16 Ink4 [77], and p57 Kip2 [126] leads to an irreversible cell cycle arrest and promotes cellular senescence. p53 levels also regulate the balance between differentiation, proliferation, and quiescence in MuSCs [127]. Controlling p53 expression improves the proliferative capacity of MuSCs in certain diseases [124].…”

Quiescence: Good and Bad of Stem Cell Aging

“…These include stem cell-intrinsic signaling pathways and epigenetic regulators as well as components of the micromilieu and the blood-circulatory environment [7][8][9]. Overarching principles of quiescence maintenance have been identified involving the expression of cell cycle inhibitors like p21 and p57 [10][11][12] as well as tumor suppressor genes like RB and p53 [13][14][15][16] in stem cells of different organs/tissues ( Figure 1).…”

SDC3 acts as a timekeeper of myogenic differentiation by regulating the insulin/AKT/mTOR axis in muscle stem cell progeny

“…An observation apparently at odds with the pro-differentiative effect of SDC3 downregulation upon differentiation initiation is that SDC3 appears to inhibit FGF2 and HGF signaling via ERK1/2 (Cornelison et al (2004) and Figure 1C) and thus, loss of SDC3 expression during the later stages of myogenesis should lead to ERK1/2 hyperactivation, but this would inhibit differentiation (Knight and Kothary, 2011) while we observe enhanced differentiation when SDC3 is absent or heavily depleted. In reality, expression of ERK1/2 is also rapidly downregulated with the onset of differentiation (Flamini et al, 2018), therefore positive regulation of ERK1/2 activity in the absence of SDC3 is only relevant during the early, proliferative stages of myogenesis, but not during the late, differentiative stages of myogenesis. Moreover, the overall heparan sulfate complement of MuSC progeny changes upon differentiation onset, becoming inhibitory for FGF2 signaling via ERK1/2 (Ghadiali et al, 2016).…”

“…In contrast, ERK1/2 phosphorylation did not increase upon SDC3 loss in differentiating myoblasts, either under basal conditions or in response to insulin, although insulin stimulation caused a reduction in ERK1 phosphorylation in differentiating myoblasts, regardless of SDC3 expression ( Figure 5J-K). This was not surprising since a reduction in ERK1/2 signaling is known to accompany myoblast differentiation (Flamini et al, 2018;Jones et al, 2001).…”