Adipose-derived stem cells (ADSCs)-derived DKK1 promotes cutaneous wound healing by inducing M2 macrophage...

Wound healing requires the coordinated resolution of inflammation and tissue regeneration, whereby the role played by macrophage polarization is critical. This study investigates whether adipose-derived stem cells (ADSCs) promote wound repair through paracrine dickkopf-related protein 1 (DKK1) and explores their regulatory mechanism on macrophage polarization. In a murine full-thickness skin wound model, ADSCs treatment significantly enhanced re-epithelialization, collagen deposition, and Ki67 expression levels, while reducing local inflammatory cytokines and promoting M2 macrophage polarization. In vitro, ADSCs suppressed proinflammatory cytokines and induced M2 markers in LPS/IFN-γ-stimulated macrophages, an effect that was attenuated upon DKK1 knockdown. Mechanistically, DKK1 enhanced PI3K/AKT and JNK pathway activation both in macrophages and wound tissue. DKK1-deficient ADSCs showed a diminished ability to promote wound healing, reduce inflammation, and modulate macrophage phenotypes. These findings identify DKK1 as a key paracrine mediator of ADSCs-driven immunomodulation and tissue regeneration, thereby providing new insights into optimizing stem cell-based therapies for wound healing.