Diabetes ranks as the third most prevalent chronic disease and poses a severe threat to global health, with approximately 415 million individuals affected worldwide [1,2]. Each year, approximately 2% of diabetic patients develop foot ulcers, and 14–24% of these patients ultimately require amputation [3]. Standard management strategies for diabetic foot ulcers include glycemic control, enhancement of vascularization, debridement, total contact casting, offloading, and the application of appropriate wound dressings [2]. Despite these interventions, a substantial number of patients fail to achieve wound healing [4]. The primary factors contributing to delayed wound healing in diabetic patients include inadequate blood supply, deficient growth factors, excessive inflammation, and microcirculatory dysfunction [5]. Consequently, diabetic wound healing represents an urgent clinical challenge.

Changes in the local microenvironment, especially the high-glucose microenvironment, cause some cellular elements and other factors in the local necrotic tissue to change, which affects the development of ulcers and ultimately results in diabetic wounds [6,7]. Recent studies have demonstrated that hyperglycemia can increase the expression of proinflammatory cytokines, inducing oxidative stress in nerve cells and contributing to neuropathy [8]. Additionally, hyperglycemia promotes the glycation of hemoglobin and the narrowing of blood vessels, resulting in impaired oxygen delivery to wounded tissues [9]. These pathogenic processes further complicate the wound microenvironment and prevent diabetic wounds from undergoing normal wound healing. Instead, the wound may stagnate in the long-term inflammatory phase, leading to the formation of nonhealing chronic wounds [10]. Furthermore, the disordered release of cytokines fails to effectively promote healing, as wound repair is a complex process that is dependent on coordinated cellular functions and specific cytokine activity.

Stem cells, particularly mesenchymal stem cells (MSCs), are increasingly employed in skin regeneration and wound healing [11]. Among them, adipose-derived mesenchymal stem cells (ADMSCs), which originate from adipose tissue and share similarities with bone marrow-derived MSCs, have gained considerable attention because of their high availability, convenient collection, minimal associated damage, high stem cell yield, low ethical concerns, low immunogenicity, and reduced immunogenicity [12]. Studies have demonstrated that ADMSCs play crucial roles in the healing of full-thickness skin defects [13], diabetic foot ulcers [14], and thermal injuries [15]. However, most of these therapeutic applications have utilized unsorted populations of ADMSCs, with limited research focusing on the use of purified ADMSC subsets in either in vitro or in vivo settings.

ADMSCs cultured in vitro exhibit diverse immunophenotypic profiles but lack a definitive marker [16]. Most ADMSCs cultured in monolayers lack one or more MSC surface markers, and CD73 expression frequently decreases [17]. Our preliminary experiments revealed that CD73 expression is highly heterogeneous and inversely correlated with culture duration, as CD73 expression is downregulated during the early stages of MSC differentiation [18]. On the basis of these observations, we hypothesize that CD73 may serve as a sensitive and reliable marker for characterizing ADMSCs. CD73, an ecto-5′-nucleotidase, is a glycoprotein widely expressed on cell membranes that has dual functions in terms of enzymatic activity and signal transduction [19]. Research has demonstrated that CD73 can promote cell proliferation and enhance clonogenic capacity [20]. In the context of oncology, CD73 has been found to promote angiogenesis under hypoxic conditions and to interact with various cytokines to support immune evasion in tumor cells [21]. However, the influence of CD73 expression on the therapeutic potential of ADMSCs in diabetic skin injuries, as well as its underlying mechanisms, remains to be elucidated.

In this study, we hypothesized that the high expression of CD73 could promote enhanced wound healing in diabetic mice. We propose that the impaired angiogenesis effects resulting from microenvironment disturbances in diabetic pressure ulcers could be rescued by CD73+ ADMSCs therapy. The primary objective of this research was to elucidate the impact of CD73 expression on the therapeutic efficacy of ADMSCs in the context of diabetic skin injuries, thereby providing a theoretical and experimental foundation for the clinical application of CD73+ ADMSCs.