Schwann cell-derived EVs facilitate dental pulp regeneration through endogenous stem cell recruitment via SDF-1/CXCR4 axis

The dental pulp is critical for physiological vitality of the tooth, and dental pulp regeneration has great potential for rebuilding live pulp tissue after pulp disease. Schwann cells (SCs) play a critical role in the support, maintenance, and regeneration of nerve fibers in dental pulp. Extracellular vesicles (EVs), which possess cell homing and tissue repair potential, derived from SCs (SC-EVs), can regulate dental mesenchymal stem cells (MSCs) proliferation, multipotency, and self-renewal. However, the role of SC-EVs in dental pulp tissue regeneration remains unclear. To address this question, we treated dental pulp stem cells (DPSCs) and bone marrow stem cells (BMSCs) with SC-EVs, and the results showed an obvious increase in the proliferation, migration, and osteogenic differentiation of both cell types. SC-EVs also promoted neurite outgrowth and neuron migration of rat dorsal root ganglia, as well as vessel formation in vitro. In an in vivo model of subcutaneous, SC-EVs enhanced the recruitment of endogenous vascular endothelioid-like cells and MSCs, and promoted the formation of a pulpo-dentinal complex-like structure. Finally, mass spectrometry analyses and western blot revealed that stromal cell-derived factor 1 (SDF-1, also known as CXCL12) plays a dominant role in SC-EVs. Together, these data suggest that SC-EVs successfully recruit endogenous stem cells to promote dental pulp regeneration. Our results provide a cell-free strategy for pulp regeneration that avoids the risks associated with stem cell transplantation.