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

Adhesion between stem cells and their niche provides stable anchorage and signaling cues to sustain properties such as quiescence. Skeletal muscle stem cells (MuSCs) adhere to an adjacent myofiber via cadherin-catenin complexes. Previous studies on N- and M-cadherin in MuSCs revealed that while N-cadherin is required for quiescence, they are collectively dispensable for MuSC niche localization and regenerative activity. Although 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 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. Combined in vivo, ex vivo, and single cell RNA sequencing approaches reveal that MuSC attrition occurs via 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 MuSC maintenance.