Identification and characterization of NFATc1⁺ skeletal stem cells in bone regeneration

Skeletal stem cells (SSCs) fuel adult bone with stemness resources to maintain homeostasis and support regeneration, which depends on the precise determination of the osteogenic lineage commitment of SSCs. In this study, using Cre-loxP reporter lineage tracking, we identified and characterized a population of NFATc1⁺ SSCs in bone regeneration. Pre-existing NFATc1⁺ SSCs are involved in early bone callus formation. Subsequently, these NFATc1⁺ SSCs produce osteolineage descendants in the subsequent stages of regeneration. The Ca²⁺-triggered transcriptional activity of NFATc1 constitutes the pre-imprinted memory of the trajectory to intrinsically orchestrate osteogenesis of SSCs. Inhibition of Ca²⁺/NFATc1 signaling in SSCs directly impairs osteogenesis and bone regeneration. In summary, our findings provide a mechanistic understanding of adult bone regeneration through the regulation of NFATc1⁺ SSCs.