iPSC-derived exosomes promote diabetic wound healing by attenuating inflammatory responses

Abstract

Background: Owing to impaired glucose metabolism, the high-glucose microenvironment in diabetic patients disrupts a series of biological reactions that hinder the wound healing process, resulting in a significant cost to the health care system and an urgent need for new and advanced therapies. Methods: In this study, induced pluripotent stem cell-derived exosomes (iPSC-Exos) were isolated from iPSC culture supernatant via centrifugation and ultrafiltration. We evaluated the therapeutic effects of iPSC-Exos on diabetic wound healing through two clinically relevant animal models (spontaneous genetic diabetic mouse model and streptozotocin (STZ)-induced diabetic mouse model). iPSC-Exos were topically administered to full-thickness cutaneous wounds in diabetic mice. The therapeutic effects were systematically assessed by measuring wound closure rates, conducting comprehensive histopathological evaluations, and performing quantitative analysis of inflammatory mediators via ELISA. Results: We demonstrated that iPSC-Exos can significantly accelerate diabetic wound healing through two clinically relevant animal models (spontaneous genetic diabetic mouse model and STZ-induced diabetic mouse model) for the first time. The multifaceted therapeutic mechanisms include: (i) Direct activation of tissue regeneration (promotion of re-epithelialization, tissue remodeling and scar attenuation); (ii) Modulation of the inflammatory microenvironment (promoting macrophage polarization toward anti-inflammatory M2 phenotype/suppressing inflammation). Conclusions: This dual-animal model approach, which closely recapitulates key pathophysiological features of human diabetic wounds, offers superior clinical translatability compared to single-animal model studies. Our findings iPSC-derived exosomes promote diabetic wound healing by attenuating inflammatory responses.

1. Introduction

Diabetes mellitus is a metabolic disease characterized by a relative or absolute lack of insulin secretion leading to chronically increased blood glucose levels [1–3]. The core mechanism of diabetic wound healing impairment is governed by a vicious cycle, driven by hyperglycemia and involving multiple interconnected components. This cycle, initiated by systemic pathophysiological disturbances, propagates through the disruption of the local microenvironment, and ultimately leads to a halt in cellular repair processes. Chronic hyperglycemia, as the initial driving factor, exerts its effects through two primary pathways: On one hand, it activates the polyol, hexosamine, and protein kinase C (PKC) pathways, triggering oxidative stress and accumulating advanced glycation end products (AGEs). This cascade further damages nerves and blood vessels: neuropathy impairs wound sensory perception and disrupts the skin barrier, increasing the risk of occult injuries [4–6]; meanwhile, angiopathy leads to insufficient blood perfusion, laying the groundwork for subsequent hypoxia and ischemia [7, 8]. On the other hand, hyperglycemia directly impairs the chemotactic and phagocytic capabilities of immune cells, reducing the efficiency of bacterial clearance and creating favorable conditions for infection.

Against this backdrop, the wound microenvironment deteriorates further: hyperglycemia upregulates the expression of pro-inflammatory factors through epigenetic modifications, promoting the sustained polarization of M1-type macrophages. Concurrently, it delays the clearance of neutrophils, forming an “inflammation-oxidative stress” cycle that induces senescence in repair cells such as fibroblasts and endothelial cells [9]. Angiopathy, combined with the high oxygen consumption of inflammatory cells, exacerbates hypoxia; however, hyperglycemia downregulates the hypoxia-inducible factor-1 (HIF-1)/vascular endothelial growth factor (VEGF) axis, inhibiting angiogenesis. Ischemia and hypoxia further worsen energy supply, hindering the proliferative phase of wound healing [7, 8, 10]. Additionally, the hyperglycemic environment facilitates bacterial colonization and biofilm formation, which stimulate the secretion of pro-inflammatory factors and exogenous proteases; this, together with the imbalance between upregulated expression of endogenous matrix metalloproteinases (MMPs) and downregulated expression of tissue inhibitors of metalloproteinases (TIMPs), collectively degrades the extracellular matrix (ECM) and growth factors, leading to tissue necrosis [11]. Additionally, chronic inflammation and infection also render the wound microenvironment alkaline (elevated pH), which further enhances MMP activity and inhibits fibroblast function [12–14], forming a self-perpetuating “microenvironment deterioration loop” [7, 8]. Eventually, the wound remains stagnant in the inflammatory phase for an extended period, unable to progress through the normal proliferative and remodeling phases of healing, thus developing into a chronic non-healing wound [15]. Traditional wound treatments, such as local dressings, blood glucose control, skin grafting, and laser therapy, have shown limited therapeutic efficacy and may carry various risks, including poor adherence to blood glucose control, donor-site damage and hyperpigmentation issues [16, 17]. Given the serious health problems associated with diabetic skin injuries and the limitations of existing treatments, the development of new and more effective technologies and strategies is of significant clinical importance for effectively promoting diabetic wound healing in light of current health trends.