Bridging skeletal stem cell diversity and human skeletal modeling

Area of Science:

• Skeletal Biology
• Regenerative Medicine
• Stem Cell Research

Background:

• Skeletal stem cells (SSCs) are crucial for skeletal development, maintenance, and repair, exhibiting heterogeneity across different anatomical sites and life stages.
• While mouse models have identified various SSC populations and their niche regulations, translating these findings to humans is hindered by species differences and limited access to human skeletal tissues.

Purpose of the Study:

• To review the current understanding of SSC diversity and their roles in skeletal formation and maintenance throughout life.
• To summarize and evaluate emerging human skeletal modeling strategies for reconstructing skeletal components and SSC niches.

Main Methods:

• Synthesis of current literature on skeletal stem cell diversity and function.
• Evaluation of human skeletal modeling strategies: pluripotent stem cell differentiation, bioengineered in vitro systems, and in vivo transplantation.
• Analysis of the ability of current models to recapitulate physiological SSC behavior and skeletal functions.

Main Results:

• Existing models often reproduce only specific skeletal compartments (e.g., perichondrium-like layers, bone marrow-like microenvironments).
• Current models generally lack integrated, stage-aware architectures necessary to fully replicate in vivo SSC behavior and skeletal functions.
• Significant challenges remain in creating models that accurately reflect the complexity and dynamism of human skeletal stem cell niches.

Conclusions:

• An SSC-centric framework is proposed, emphasizing spatiotemporal diversity, multi-compartment integration, and physiological cues.
• This framework aims to provide predictive and translational platforms for skeletal biology, disease modeling, and regenerative medicine.
• Cross-validation with human tissues is essential for developing effective skeletal regenerative strategies.