Adipocyte Kindlin-2 Coordinates an E-cadherin/β-catenin/IGFBP2 Endocrine Axis to Regulate Skin Regeneration and Diabetic Wound Healing

Skin wound healing is a complex, multicellular process essential for maintaining tissue integrity and homeostasis. Despite advances in biomaterial and cell-based therapies, the mechanisms by which adipose tissue regulates skin regeneration remain incompletely understood. Here, we identify adipocyte Kindlin-2 as a critical regulator of cutaneous wound repair. Adipocyte-specific deletion of Kindlin-2 markedly accelerates wound closure in mice by enhancing fibroblast proliferation, angiogenesis, and suppressing inflammation. Transplantation of visceral white adipose tissue (vWAT) from Kindlin-2-deficient mice similarly promotes wound healing, indicating an endocrine contribution of vWAT to skin regeneration. Mechanistically, loss of Kindlin-2 promotes E-cadherin proteolysis, resulting in increased release of a 33-kDa C-terminal fragment (CTF2) that activates {beta}-catenin signaling and induces transcriptional upregulation and secretion of insulin-like growth factor binding protein 2 (IGFBP2). Elevated circulating IGFBP2, in turn, stimulates integrin signaling in target cells to enhance wound repair. Pharmacological inhibition of {beta}-catenin signaling abrogated the healing advantage conferred by Kindlin-2 deficiency. Conversely, local delivery of IGFBP2 via lentiviral significantly accelerates wound closure in both wild-type C57BL/6 and diabetic ob/ob mice. Collectively, these findings uncover a previously unrecognized adipose-skin endocrine axis governed by Kindlin-2 and IGFBP2 that orchestrates tissue regeneration. Targeting this Kindlin-2/E-cadherin/{beta}-catenin/IGFBP2 pathway offers a promising therapeutic strategy for enhancing wound healing, particularly in chronic and diabetic wounds.

Ding, Z., Ma, G., Wang, F., Cheng, S., Li, P., Chen, Y., Chen, L., Ouyang, M., Wu, A., Pan, H., Cao, H.

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