Human skeletal development and regeneration are shaped by functional diversity of stem cells across skeletal sites
Thomas H. Ambrosi, Sahar Taheri, Kun Chen, Rahul Sinha, Yuting Wang, Ethan J. Hunt, L. Henry Goodnough, Matthew P. Murphy, Holly Steininger, Malachia Hoover, Franco Felix, Kelly C. Weldon, Lauren S. Koepke, Jan Sokol, Daniel Dan Liu, Liming Zhao, Stephanie D. Conley, Wan-Jin Lu, Maurizio Morri, Norma Neff, Noelle L. Van Rysselberghe, Erika E. Wheeler, Yongheng Wang, J. Kent Leach, Augustine M. Saiz, Aijun Wang, George P. Yang, Stuart B. Goodman, Julius A. Bishop, Michael J. Gardner, Derrick C. Wan, Irving L. Weissman, Michael T. Longaker, Debashis Sahoo, Charles K. F. Chan
Abstract
) from ten skeletal sites with functional assays and single-cell RNA sequencing (scRNA-seq) analysis to identify chondrogenic, osteogenic, stromal, and fibrogenic subtypes of hSSCs during development and their linkage to skeletal phenotypes. We map the distinct composition of hSSC subtypes across multiple skeletal sites and demonstrate their unique in vivo clonal dynamics. We find that age-related changes in bone formation and regeneration disorders stem from a pathological fibroblastic shift in the hSSC pool. Utilizing a Boolean algorithm, we uncover gene regulatory networks that dictate differences in the ability of hSSCs to generate specific skeletal tissues. Importantly, hSSC lineage dynamics are pharmacologically malleable, providing a new strategy to treat aberrant hSSC diversity central to aging and skeletal maladies.