Lean adipose tissue macrophage derived exosome confers immunoregulation to improve wound healing in diabetes

Abstract

Chronic non-healing wounds, a prevalent complication of diabetes, are associated with increased mortality in diabetic patients. Excessive accumulation of M1 macrophages in diabetic wounds promotes inflammation and results in dysregulated tissue repair. Adipose tissue macrophages (ATMs) derived from healthy lean donors have the ability to improve glucose tolerance and insulin sensitivity, as well as modulate inflammation. MicroRNAs (miRs), which can be packaged into exosomes (Exos) and secreted from cells, serve as essential regulators of macrophage polarization. Here, we revealed that ATMs isolated from lean mice secrete miRs-containing Exos, which modulate macrophage polarization and promote rapid diabetic wound healing when administered to diabetes-prone db/db mice. The miRs sequence of tissue samples from wounds treated with Exos secreted by lean ATMs (ExosLean) revealed that miR-222-3p was up-regulated. Further analyses showed that inhibiting miR-222-3p using a miR inhibitor impaired the macrophage-reprogramming effect of ExosLean. In the excisional skin wound mouse model, locally inhibiting miR-222-3p disrupted healing dynamics and failed to modulate macrophage polarization. Mechanistic studies revealed a connection between miR-222-3p, Bcl2l11/Bim, an inflammatory response effector, macrophage polarization, and diabetic wound healing. In summary, ExosLean act as positive regulators of macrophage polarization by regulating miR levels in wounds and accelerating wound healing, and thus have important implications for wound management in diabetes. Graphic Abstract

Preparation of a Dual-Functional Sulfated Galactofucan Polysaccharide/Poly(vinyl alcohol) Hydrogel to Promote Macrophage Recruitment and Angiogenic Potential in Diabetic Wound Healing

“…Macrophages have distinct phenotypes and functions that are essential for healing. They are involved in host defense, inflammation activation and resolution, growth factor production, phagocytosis, cell proliferation, and wound tissue restoration. , Macrophage accumulation in the early stage of inflammation is important, and CCL2 is an important and powerful macrophage chemoattractant during the early inflammatory process. Topical administration of CCL2 immediately after the injury may accelerate the wound closure rates by recruiting macrophages, enhancing the neovascularization, and collagen accumulation in the model of diabetic mice .…”

Exosomes: The emerging mechanisms and potential clinical applications in dermatology

“…Macrophage-derived exosomes accelerated diabetic wound healing by inducing angiogenesis, enhancing cell bioactivity, and inhibiting inflammatory cytokines 78 . Lean adipose tissue macrophage-derived exosomes promoted M2 macrophage polarization to improve diabetic wound healing via transferring miR-222-3p to inhibit Bim expression in mice 79 . ESC-exos induced M2 macrophage polarization to promote diabetic wound healing via miR-203a-3p/SOCS3-mediated JAK2/STAT3 signaling activation 80 .…”

Exosomes Derived from Adipose Stem Cells Enhance Angiogenesis in Diabetic Wound Via miR-146a-5p/JAZF1 Axis

“…MiRNAs are well-established inducers of translational repression and mRNA decay. The role of exosomes and miRNAs in regenerative medicine is gradually unfolding [ 12 , 13 ]. However, the precise mechanisms by which exosomes exert their effects through miRNAs in the healing process of traumatic injuries warrant further investigation.…”