Fibronectin Potentiates Topical Erythropoietin-Induced Wound Repair in Diabetic Mice

Abstract

Diabetes mellitus disrupts all phases of the wound repair cascade and leads to development of chronic wounds. We previously showed that topical erythropoietin (EPO) can promote wound repair in diabetic rats. Fibronectin (FN) has a critical role throughout the process of wound healing, yet it is deficient in wound tissues of diabetic patients. Therefore, we investigated the effect of topical treatment of both EPO and FN (EPO/FN) on wound repair in diabetic mice. Full-thickness excisional skin wounds in diabetic and nondiabetic mice were treated with a cream containing vehicle, EPO, FN, or EPO/FN. We assessed the rate of wound closure, angiogenesis, apoptosis, and expression of inflammatory cytokines, endothelial nitric oxide synthase (eNOS) and β1-integrin, in the wound tissues. We also investigated the effect of EPO, FN, and EPO/FN on human dermal microvascular endothelial cells and fibroblasts cultured on fibrin-coated plates, or in high glucose concentrations. EPO/FN treatment significantly increased the rate of wound closure and this effect was associated with increased angiogenesis, increased eNOS and β1-integrin expression, and reduced expression of inflammatory cytokines and apoptosis. Our findings show that EPO and FN have an additive effect on wound repair in diabetic mice.

Fibronectin Matrix Mimetics Promote Full-Thickness Wound Repair in Diabetic Mice

“…58 Similarly, full-length fibronectin potentiates effects of erythropoietin treatment on wound healing in diabetic mice. 33 As such, fibronectin matrix mimetics could serve as a supplement to other treatment strategies to enhance healing of chronic wounds. The small size of the recombinant fibronectin proteins facilitates production, decreases potential immunogenicity, and provides increased structure and stability compared with peptides.…”

“…31 The wound area immediately after surgery (Day 0) was referred to as the original wound area, and all subsequent wound areas were recorded as a percentage of the original area, as previously described. [32][33][34] Wound closure is presented as ''Percent Closure'' and was determined as follows:…”

Notoginsenoside Ft1 Promotes Fibroblast Proliferation via PI3K/Akt/mTOR Signaling Pathway and Benefits Wound Healing in Genetically Diabetic Mice

“…Some of the fibroblasts in the injured tissue may differentiate into a highly contractile phenotype, i.e., myofibroblasts (Ross et al, 1970;Gabbiani, 1996),which have bundles of a-smooth muscle actin (SMA) contributing to the closure of wound (Gabbiani, 2003;Lanning et al, 2000). Collagen and fibronectin are important components of granulation tissue, contributing to its integrity and delivery of tethered growth factors (Park et al, 2005;Hamed et al, 2011). Proteins in TGF-b family attract macrophages into the wound area and stimulate them to produce additional cytokines, which further enhance fibroblast and smooth muscle chemotaxis and modulate collagen expression as well as consequent scar formation (Beldon, 2010).…”

Erythropoietin Restores C-Fiber Function and Prevents Pressure Ulcer Formation in Diabetic Mice

“…The ability of systemic administration of EPO to accelerate wound closure in various models of skin excision , such as burns (Galeano et al, 2006) and ischemic wounds (Buemi et al, 2004), has been reported repeatedly. This effect appears to be independent of hematocrit changes as the non-erythropoietic, tissue-protective derivatives, carbamylated EPO and ARA 290, are highly effective in facilitating wound healing (Erbayraktar et al, 2009), and as topical administration of (Hamed et al, 2010(Hamed et al, , 2011. However, wound repair and formation of ulcers in response to pressure are clearly distinct processes, so that the beneficial mechanisms of EPO in both settings are not necessarily the same.…”