Muscle stem cell niche localization, quiescence, and maintenance are cadherin-dependent but separable functions

Adhesion between stem cells and their niche promotes stable niche localization and provides signaling information to sustain properties such as quiescence. Skeletal muscle stem cells (MuSCs) are localized between an adjacent myofiber and an enwrapping basal lamina. The most abundant cadherin in MuSCs, M-cadherin, is dispensable for MuSC function, whereas N-cadherin is required to prevent MuSCs from breaking quiescence in the absence of injury. Loss of both cadherins exacerbates this phenotype, yet the MuSCs remain in the niche and maintain regenerative function. These findings raise the possibility that cadherins are dispensable for anchorage of MuSCs to their niche. To address this question, we conditionally removed from MuSCs b- and g-catenin and, separately, aE- and aT-catenin, factors essential for cadherin-dependent adhesion. Catenin-deficient MuSCs break quiescence similarly to N-/M-cadherin-deficient MuSCs, but exit the niche, and are depleted via a single fate: precocious differentiation, reentry to the niche, and fusion to myofibers. These findings indicate that separable, cadherin-dependent functions are required in MuSCs for niche localization, quiescence, and stem cell maintenance. Skeletal muscle stem cells (MuSCs)of Ctnna1fl/fl;Ctnna3fl/fl;Pax7CreERT2/+;Rosa26-tdTomato+ and Pax7CreERT2/+;Rosa26-tdTomato+ mice were isolated by Fluorescence-activated cell sorting (FACS) according to the presence or absence of tdTomato signal and analyzed using scRNAseq.