MSC have shown efficacy in multiple clinical trials of DFU healing and are currently included in several commercially available topical products including Grafix and Stravix. Adult-derived cells, such as mesenchymal stem cells (MSC), have shown potential in accelerating healing of chronic wounds, particularly in the diabetic population where populations of MSC are deficient. When transplanted into a wound, stem cells act in a direct and paracrine manner to promote cell recruitment, immunomodulation, extracellular matrix remodeling, and angiogenesis by secretion of cytokines and growth factors. Stem cell therapy has emerged as an exciting potential therapy for wound healing. As such, novel and improved methods of wound healing are urgently needed. Despite optimal care, only 50% of DFU heal within 12–20 weeks and 50% recur within 18 months. The gold standard of chronic wound management involves careful diagnosis of etiology, control of infection, optimization of vascular inflow to reduce ischemia, debridement of nonviable tissue, and offloading of pressure. Diabetic individuals suffer from impaired growth factor production, decreased angiogenesis, depressed macrophage function and collagen accumulation, poor keratinocyte and fibroblast migration and proliferation, and impaired stem cell homing. Nearly every stage of wound healing becomes dysregulated in diabetic wounds, contributing to the poor healing of DFU. They affect over six million Americans annually and cost upwards of $25 billion. Ĭhronic cutaneous wounds, such as those seen in diabetic foot ulcers (DFU) and pressure ulcers, contribute significantly to patient morbidity and mortality. During these events, angiogenesis results in re-vascularization of the wound. Eventually, fibroblasts convert fibronectin-based microfibrils into collagen-enriched fibers. A provisional matrix composed of fibronectin and hyaluronic acid (HA) is synthesized and secreted, upon which epithelialization occurs with the aid of stem cells from hair follicles and adjacent epidermis. Neutrophils and macrophages clear the wound of any bacteria and debris and elaborate further cytokines including interleukin 1 (IL-1), vascular endothelial growth factor (VEGF), and tumor necrosis factor alpha (TNF-α), all of which promote cellular recruitment and proliferation. Chemotactic signals including platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) are released and attract macrophages, neutrophils, and fibroblasts to the wound bed. Immediately post-wounding, hemostasis is achieved by platelet aggregation and initiation of the coagulation cascade. This complex and delicate process is prone to dysregulation secondary to local and systemic factors that can lead to failure of healing and progression to chronicity. It involves the spatial and temporal coordination of various cell types and cytokines and is divided into three distinct phases: inflammation, proliferation, and remodeling. Wound healing is a complex physiological response to the disruption in the normal architecture of the protective skin barrier. This review focuses on the use of iPSC in animal models of wound healing including limb ischemia, as well as their limitations and methods aimed at improving iPSC safety profile in an effort to hasten translation to human studies. iPSC are derived from adult cells by in vitro induction of pluripotency, obviating the ethical dilemmas surrounding the use of embryonic stem cells they are harvested non-invasively and can be transplanted autologously, reducing immune rejection and iPSC are the only cell type capable of being differentiated into all of the cell types in healthy skin. Induced pluripotent stem cells (iPSC) are an exciting cell type with enhanced therapeutic and translational potential. Stem cell therapy is emerging as a potential treatment for chronic wounds, and adult-derived stem cells are currently employed in several commercially available products however, stem cell therapy is limited by the need for invasive harvesting techniques, immunogenicity, and limited cell survival in vivo. Chronic wounds such as diabetic foot ulcers are epidemic with great cost to the healthcare system as they heal poorly and recur frequently, creating an urgent need for new and advanced therapies. This complex process is prone to dysregulation secondary to local and systemic factors such as ischemia and diabetes that frequently lead to chronic wounds. Wound healing is the physiologic response to a disruption in normal skin architecture and requires both spatial and temporal coordination of multiple cell types and cytokines.
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