Diabetes mellitus is a group of chronic metabolic diseases worldwide that seriously threaten human health and increases the social and economic burden; underlying drivers of impaired healing include uncontrolled inflammation, repeated ischemia reperfusion injury, and neuropathy alongside infection risks. Macrophages orchestrate standard repair, exhibit sustained classical pro-inflammatory activation in diabetes, disrupting growth factor secretion, angiogenesis, and matrix regulation. Hyperglycemia mediated advanced glycation end products and reactive oxygen species heighten pattern recognition receptor stimulation, causing reduced alternative macrophage differentiation. Promising immunomodulation approaches redirecting their phenotypes to resolve inflammation and stimulate regeneration provides optimism. We discuss macrophage origination, polarization dynamics, diabetic wounds phenotypic imbalance, and critical microenvironmental disruptions perpetuating pathological function. Elucidating specific regulatory nodes upholding their activation states will inform intelligent targeting opportunities. Overall, infiltrating macrophages constitute indispensable yet amenable diabetic wound healing coordinators.
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To investigate the mechanisms underlying the reduced biomechanical properties and impaired wound healing in the dorsal skin of streptozocin (STZ)-induced type 1 diabetes mellitus (T1DM) mice.
Forty male C57BL/6 mice (8 weeks old, weighing 20~25 g) were randomly divided into wild-type (WT, n=20) and T1DM (n=20) groups. After the mice were inflicted with full-thickness skin resection (circular, 1 cm in diameter, in both sides of the back midline), atomic force microscopy (AFM) and scanning electron microscopy (SEM) were employed to assess the Young's modulus, relaxation rate, and collagen arrangement of the skin, and HE, Masson's trichrome, Sirius red, Gordon-Sweet, and Victoria blue staining were all applied to evaluate the epidermis and granulation tissue, total collagen content, ratio of type Ⅲ to type Ⅰ collagen, reticular fiber content, and elastic fiber content. Immunohistochemical assay and Western blotting were conducted to quantify the expression of type Ⅰ and type Ⅲ collagen proteins. Flow cytometry and immunofluorescence staining of paraffin sections were performed to detect the transformation of myofibroblast in wound tissues.
On day 21 post-wounding, the dorsal skin of T1DM mice exhibited significantly reduced stiffness, strength, and resilience compared to the conditions in the WT group (P<0.05). During and after healing, T1DM mice showed decreased collagen and elastic fibers, an increased ratio of type Ⅲ to type Ⅰ collagen, and increased reticular fibers, all with statistical significance (P<0.05). Additionally, there was a significant reduction in myofibroblast transformation during the early stages of wound healing in the T1DM group (P<0.05).
T1DM inhibits the transformation of fibroblasts into myofibroblasts, leading to impaired wound healing and reduced biomechanical properties in the dorsal skin of mice.
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