Effect of rhGM-CSF in Promoting Wound Healing via Macrophage Immunomodulation

Abstract Context Recombinant human granulocyte macrophage–colony stimulating factor (rhGM-CSF) is predominantly used for therapy of hematologic disorders. Emerging research suggests its efficacy in wound healing. Objective This study aims to validate the effect and molecular mechanisms of rhGM-CSF on diabetic/nondiabetic wound healing. Methods Two full-thickness wounds were created on the backs of C57BL/6J mice. The caudal wounds were treated daily with topical rhGM-CSF (1.0 μg/cm2), while the cranial wounds received saline. Also, patients with diabetic lower extremity ulcers were randomized into rhGM-CSF intervention (2.0 μg/cm2 infiltration) and control groups. The primary endpoint was the overall percentage area reduction by 1 month. The wound tissues were stained with hematoxylin and eosin and immunofluorescence. Western blots were performed to analyze macrophage subtypes. Results Topical administration of rhGM-CSF significantly accelerated wound healing in C57BL/6J mice, with an average healing rate of 2.53 ± 0.25 mm2/day. Increase in the capillary marker CD31 and the expression of vascular endothelial growth factor (VEGF)A was observed after rhGM-CSF intervention. The clinical trial included 48 subjects with comparable baseline characteristics between the rhGM-CSF (n = 27) and control (n = 21) groups. The rhGM-CSF group showed significantly greater overall percentage area reduction (97.7 ± 8.9%) vs controls (P < .05). Mechanistically, the rhGM-CSF intervention resulted in a significant reduction in M1-type macrophages and an increase in M2-type macrophages, with M2a predominating at day 5 and M2d dominating at day 10 post-injury. Conclusion Our study suggested that topical administration of rhGM-CSF can promote the healing of both diabetic and nondiabetic wounds, which is partly attributable to promoting the transformation of macrophages to M2 subtype.