Cadherin-dependent adhesion is required for muscle stem cell niche anchorage and maintenance

ABSTRACT Adhesion between stem cells and their niche provides stable anchorage and signaling cues to sustain properties such as quiescence. Skeletal muscle stem cells (MuSCs) directly adhere to an adjacent myofiber via cadherin-catenin complexes. Previous studies on N- and M-cadherin function in MuSCs revealed that while N-cadherin is required for quiescence, they are collectively dispensable for MuSC niche localization and regenerative activity. While additional cadherins are expressed at low levels, these findings raise the possibility that cadherins are unnecessary for MuSC anchorage to the niche. To address this question, we conditionally removed from MuSCs β- and γ-catenin and, separately, αE- and αT-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. A combination of in vivo, ex vivo, and single cell RNA sequencing approaches reveal that MuSC attrition occurs via a single fate: precocious differentiation, reentry to the niche, and fusion to myofibers. These findings indicate that cadherin-catenin–dependent adhesion is required for anchorage of MuSCs to their niche and preservation of the stem cell compartment. Furthermore, separable, cadherin-regulated functions govern niche localization, quiescence, and stem cell maintenance in MuSCs. SUMMARY STATEMENT Genetic ablation of cadherin-based adhesion in skeletal muscle stem cells triggers activation, niche exit, precocious differentiation, and subsequent depletion of the stem cell pool.