Enhancer-Driven Shh Signaling Promotes Glia-to-Mesenchyme Transition During Bone Repair

Schwann cells (SCs) of peripheral nerve play a critical role in vascular remodeling and osteogenic differentiation during the early stage of bone healing, and the abnormal plasticity of SCs would jeopardize the bone regeneration. However, how SCs respond to injury and initiate the vascularized osteogenesis remains incompletely understood. Here, by employing single-cell transcriptional profiling combined with lineage-specific tracing models, we uncover that a subset of Gli1+ mesenchymal stromal cells (MSCs) undergoing injury-induced glia-to-MSC transition (GMT) contributed to osteogenesis and revascularization in the initial stage of bone injury. Importantly, our data demonstrated that the Sonic hedgehog (Shh) signaling was responsible for the GMT initiation, which was strongly activated by c-Jun/SIRT6/BAF170 complex-drivenShh enhancers. Collectively, these findings depict an injury-specific niche signal-mediated SCs transition towards Gli1+MSCs and may be instructive for approaches to promote bone regeneration during aging or other bone diseases.