Wnt-presenting materials sustain H3K14-acetylation in human skeletal stem cells for tissue engineering and bone repair

Engineering functional tissues for transplantation requires insight into epigenetic mechanisms that regulate stem cell fate. We have developed the Wnt-induced osteogenic tissue model (WIOTM), a platform that recapitulates human osteogenesis, and identified acetylation of histone H3 at lysine 14 (H3K14ac) as a critical epigenetic regulator in human skeletal stem cells (hSSCs). In WIOTM, localized Wnt signals drive asymmetric cell division (ACD), yielding a proximal hSSC with high H3K14ac and a distal daughter with reduced H3K14ac that migrates into the 3D collagen matrix and initiates osteogenic differentiation. Disrupting H3K14ac in hSSCs abrogates ACD and WIOTM formation. To test whether hSSCs maintain H3K14ac in vivo, we formed the WIOTM on Wnt-functionalized polymer bandages and transplanted them into calvarial defects. The WIOTM contributed to bone repair, and human cells adjacent to the bandages retained high H3K14ac despite the injury environment. These findings establish WIOTM as both a mechanistic and translational platform for regenerative medicine.