Schwann Cell–Secreted S100B Promotes Wound Healing via Paracrine Modulation

As the supply source for gingival grafts, the palatal tissue possesses marked regenerative ability after repeated wounding over the buccal attached gingiva and skin. However, the intrinsic mechanisms are poorly understood. Schwann cells reportedly participate in wound repair of many tissues. Here, we investigate whether Schwann cells play an essential role in the wound healing of palatal mucosa. We performed multiomics analysis in nonhuman primates, integrating scRNA-seq and proteomics analysis, and built wound-healing models in the palatal mucosa and buccal attached gingiva and skin to compare the regeneration among different sites and explore the paracrine role of Schwann cells in the healing of palatal mucosa. With regard to in vivo validation, GelMA hydrogels loaded with conditional medium or exogenous protein were applied in rat and monkey skin. We revealed greater distributions and a lower differentiation state of Schwann cells in the palatal mucosa at baseline. Moreover, S100B levels were significantly greater in the wound healing of palatal mucosa than in the buccal attached gingiva, and Schwann cell–secreted S100B can promote the healing-related capabilities of fibroblasts via paracrine modulation with receptor of advanced glycation end products (RAGE), which activates the crosstalk between NF-κB and Notch signaling, leading to expedited wound closure in vivo. Our work shows that Schwann cells play a crucial role in the wound healing of the palatal mucosa through the S100B/RAGE/NF-κB/Notch paracrine axis. In addition, our data provide novel insights into the therapeutic effects of S100B protein on wound healing.