aFGF gene-modified adipose-derived mesenchymal stem cells promote healing of full-thickness skin defects in diabetic rats

Abstract

Background Chronic diabetic wounds pose a significant clinical challenge due to the limited efficacy of current treatments. This study aimed to investigate the role and potential mechanisms of adipose-derived mesenchymal stem cells (ADSCs) overexpressing acidic fibroblast growth factor (aFGF) in diabetic wound healing in a rat model. Methods ADSCs were genetically modified to achieve stable overexpression of aFGF. Varying doses of aFGF-ADSCs (1×10⁶, 2×10⁶, 3×10⁶, 4×10⁶) were injected into the muscular tissue surrounding diabetic rat wounds. We assessed aFGF expression and its impact on various stages of wound healing, including angiogenesis, inflammatory response, epithelialization, and collagen deposition. Transcriptomic sequencing was performed to explore the underlying mechanisms driving enhanced wound healing. Results Lentiviral transduction successfully induced stable aFGF overexpression in ADSCs. In vivo experiments revealed that varying doses of aFGF-ADSCs markedly enhanced wound healing in diabetic rats in a dose-dependent manner. The dose of 3×10⁶ aFGF-ADSCs demonstrated the most significant effect. In the 3×10⁶ aFGF-ADSCs group, expression levels of aFGF, CD31, and CD163 were significantly higher than in other groups (p < 0.05), while CD86 expression was significantly lower (p < 0.05). Conclusion Single doses of aFGF-ADSCs comprehensively improved various aspects of wound repair in diabetic rats, offering a potential new approach for treating chronic diabetic wounds. The mechanism of action involves promoting angiogenesis, modulating inflammatory responses, accelerating epithelialization, and optimizing collagen deposition.

1. Introduction

The skin, as the largest organ in the human body, serves as a natural physical barrier against external stimuli [1]. Normal wound healing commences with blood coagulation and activation of inflammatory cells, followed by proliferation and migration of fibroblasts and keratinocytes, along with matrix deposition and angiogenesis [2]. Chronic wounds are defined as long-term injuries that fail to achieve complete anatomical and functional repair through normal healing processes after one month of clinical treatment [3, 4]. Various diseases or specific injuries can impede wound healing, notably diabetes, which disrupts the typically ordered and overlapping healing process. Common characteristics of chronic wounds include persistent bacterial biofilms, defective epithelial regeneration, reduced angiogenesis, and delayed extracellular matrix (ECM) remodeling [5, 6]. In the United States, annual medical expenditures related to wound care are estimated to range between $31.7 billion and $96.8 billion [7]. Traditional treatments for chronic, non-healing wounds include wound cleaning and dressing changes, local or systemic antibiotic application, various physical therapies, and skin grafting or flap transplantation when feasible. However, these treatments often yield unsatisfactory results due to the persistent and complex pathophysiological features of chronic wounds.

In recent years, many scholars domestically and internationally have proposed and applied new treatment concepts and methods for chronic, non-healing wounds. Particularly, numerous novel bioengineered artificial skin products have gained attention in wound repair. Research on bioengineered artificial skin primarily involves three aspects: seed cells, scaffold materials, and growth factors, which work synergistically to promote wound repair [8]. Seed cells provide a vital source for scaffold materials and can form cells with functional tissue properties [9]. Common stem cells in wound repair include epidermal stem cells, dermal stem cells.