FOXM1 accelerates wound healing in diabetic foot ulcer by inducing M2 macrophage polarization through a mechanism involving SEMA3C/NRP2/Hedgehog signaling

Abstract

Aims: The diabetic wound environment is accompanied with prolonged inflammation leading to impaired wound healing in diabetic foot ulcer (DFU). Our study illustrated the molecular mechanisms by which Forkhead box M1 (FOXM1) enhanced M2 polarization and wound healing of DFU.

Methods: Diabetes was modeled in vivo by streptozotocin injection in rats and in vitro by exposure to high glucose in human dermal fibroblasts (HDF). Macrophages were exposed to IL-4 to induce M2 phenotype polarization. Ectopic expression or knockdown of FOXM1 was performed to observe collagen deposition, angiogenesis, the proliferation and migration of HDF, as well as macrophage polarization.

Results: FOXM1 was lowly expressed in the wound tissue of DFU rats. In vitro experiments showed that silencing FOXM1 reversed the M2 polarization-induced promotion of HDF proliferation and migration. We further found that FOXM1 bound to the promoter region of SEMA3C to elevate its expression, and SEMA3C upregulated NRP2 and activated the Hedgehog signaling pathway. Silencing of SMO, a signal transducer in the Hedgehog pathway, negated the promoting effect of FOXM1 overexpression in M2 polarization and HDF proliferation.

Conclusions: Thus, our results suggest that targeting transcription factor FOXM1 may provide a therapeutic target for promoting wound healing in DFU.

Keywords: Class-3 semaphorins; Diabetic foot ulcer; Fibroblasts; Forkhead box M1; Hedgehog signaling pathway; M2 polarization; Macrophages; Neuropilin-2; Wound healing.