Stage-resolved geography of mouse skeletal stem cells.

PURPOSE: Framed as the "geography" of skeletal stem cells (SSCs), this review aims to synthesize how developmental stages and local niche cues determine SSC identity and function. Ultimately, it seeks to provide a comprehensive conceptual basis for understanding skeletal development and regeneration.

RESULT: By moving beyond early in vitro concepts of colony-forming unit fibroblasts (CFU-Fs), recent advances in in vivo lineage tracing, clonal analyses, and spatial/single-cell omics have revealed pronounced heterogeneity within marrow SSCs and identified anatomically distinct populations in the cartilage, perichondrium, and periosteum (both fibrous and cambium layers). These specific compartments display a context-dependent division of labor: perichondrial and periosteal SSCs drive bone growth and fracture healing; cartilage-embedded progenitors maintain articular and growth-plate tissues; and marrow stromal SSCs primarily support steady-state bone remodeling and hematopoiesis, while responding variably after injury.

CONCLUSION

The spatial and temporal geography of SSCs dictates their specialized roles across development, homeostasis, and repair. Mapping these anatomically distinct populations provides a crucial conceptual framework for understanding skeletal biology and developing targeted regenerative therapies.