Niche Cadherins Control the Quiescence-to-Activation Transition in Muscle Stem Cells

Abstract

SUMMARY Many adult stem cells display prolonged quiescence, promoted by cues from their niche. Upon tissue damage, a coordinated transition to the activated state is required, as non-physiological breaks in quiescence often lead to stem cell depletion and impaired regeneration. Here, we identify cadherin-mediated adhesion and signaling between muscle stem cells (satellite cells; SCs) and their myofiber niche as a mechanism that orchestrates the quiescence-to-activation transition. Conditional removal of N-cadherin and M-cadherin in mice leads to a break in SC quiescence with long-term expansion of a regeneration-proficient SC pool. These SCs have an incomplete disruption of the myofiber-SC adhesive junction, and maintain niche residence and cell polarity, yet show properties of SCs in a state of transition from quiescence towards full activation. Among these is nuclear localization of β-catenin, which is necessary for this phenotype. Injury-induced perturbation of niche adhesive junctions is therefore a likely first step in the quiescence-to-activation transition.

EGFR-Aurka Signaling Rescues Polarity and Regeneration Defects in Dystrophin-Deficient Muscle Stem Cells by Increasing Asymmetric Divisions

“…The basal surface of satellite cells attaches to the basal lamina and the apical surface to the myofiber. M-cadherin, a well-known satellite cell marker, and its partner b-catenin are localized on the apical surface and form cell-cell adherence junctions with the myofiber (Goel et al, 2017;Irintchev et al, 1994). Pard3, a member of the Par complex, is localized along the apical surface of satellite cells (Dumont et al, 2015b;Troy et al, 2012).…”

Single Cell Deconstruction of Muscle Stem Cell Heterogeneity During Aging Reveals Sensitivity to the Neuromuscular Junction

“…This is further supported by previous work demonstrating aging is associated with a loss of MuSC derived contributions in the vicinity of NMJs, a reduction in post-synaptic myonuclei, and accelerated NMJ degeneration upon MuSC depletion 17 . The attractive interaction between MuSCs and denervation requires further study, but development of filopodia has previously been observed for MuSCs 14,63 and may facilitate transport of signaling ligands 64 or local changes in cadherin signaling 65 that is critical for synaptic patterning 66 .…”

Adult stem cells at work: regenerating skeletal muscle

“…In mice lacking Notch1 and Notch2 in satellite cells, an inability to maintain quiescence can be observed, resulting in precocious entry into the cell cycle and in the end to a loss of satellite cells [73]. Cross talk of Notch signaling with the vascular niche is also important for regulating satellite cell quiescence-reminiscent of the role of cell adhesion molecules such as Cadherins, which control the transition from quiescence to activation through interaction with the myofiber niche [74,75]. The importance of the interaction of Notch with the niche is further highlighted in a recent study by Baghdadi and colleagues who show that Notch-1/RBPJ controls expression of the extracellular matrix (ECM) molecule Collagen-V [76].…”