Targeting Grancalcin Accelerates Wound Healing by Improving Angiogenesis in Diabetes

Chronic diabetic wounds are a serious complication of diabetes and often result in limb amputations and confer high mortality rates. The proinflammatory secretome in the wound perpetuates defective neovascularization and contributes to dysregulated tissue repair. This study aims to design a gelatin methacrylamide (GelMA) hydrogel to sustained the release of grancalcin-neutralizing antibody (GCA-NAb) and evaluate it as a potential scaffold to promote diabetic wound healing. Results show that the expression of grancalcin(GCA), a protein secreted by bone marrow-derived immune cells, is elevated in the wound sites of individuals and animals with diabetic ulcers. Genetic inhibition of grancalcin expression accelerates vascularization and healing in an animal model. Mechanistic studies show that grancalcin binds to transient receptor potential melastatin 8(TRPM8) and partially inactivates its downstream signaling pathways, thereby impairing angiogenesis in vitro and ex vivo. Systemic or topical administration of a GCA-NAb accelerate wound repair in mice with diabetes. The data suggest that GCA is a potential therapeutic target for the treatment of diabetic ulcers. In diabetic ulcer-afflicted mice, bone marrow-derived GCA+ immune cells release substantial amounts of grancalcin(GCA), hindering diabetic wound healing through angiogenesis inhibition. To counter this, a hydrogel embedded with GCA-neutralizing antibodies(GelMA-GCA-NAb) specifically for treating diabetic wounds is developed. Using GelMA-GCA-NAb notably expedites wound closure, augments angiogenesis, and mitigates local inflammatory responses. image