Bridging skeletal stem cell diversity and human skeletal modeling.

Abstract

Skeletal stem cells (SSCs) underlie skeletal development, homeostasis, regeneration, and aging, yet their identities and functions are highly heterogeneous across anatomical sites and life stages. Mouse genetic studies have identified multiple SSC populations-each residing in distinct niches such as the growth plate, periosteum, and bone marrow-and revealed their dynamic regulation across developmental, homeostatic, regenerative, and aging contexts. However, translating these insights to humans remains challenging due to species differences and limited access to physiological human skeletal tissues. This review synthesizes current understanding of SSC diversity and how distinct compartments contribute to skeletal formation and maintenance throughout life. It also summarizes emerging human skeletal modeling strategies, including pluripotent stem cell differentiation, bioengineered in vitro systems, and in vivo transplantation, evaluating their ability to reconstruct skeletal components and SSC-bearing niches. Although recent models reproduce partial structures such as perichondrium-like layers or bone marrow-like microenvironments, most remain compartment-specific and lack integrated, stage-aware architectures that recapitulate physiological SSC behavior and skeletal functions in vivo. We propose an SSC-centric framework that incorporates spatiotemporal diversity, multi-compartment integration, physiological cues, and cross-validation with human tissues, providing predictive and translational platforms for skeletal biology, disease modeling, and regenerative medicine.