Erythropoietin improves skin wound healing and activates the TGF-β signaling pathway

Abstract

We could recently report that erythropoietin (EPO) accelerates skin wound healing in mice. Now, we provide insight into the molecular mechanisms of this non-hematopoietic property of EPO analyzing the transforming growth factor (TGF)-b signaling pathway. EPO receptor was found expressed in both non-wounded and wounded skin tissue as well as in fibroblasts and keratinocytes. In saline-treated control animals, wounds exhibited a significant upregulation of TGF-b1 and of a-smooth muscle actin (a-SMA) compared with non-wounded skin. EPO treatment accelerated wound epithelialization and induced mRNA expression of TGF-b1 and a-SMA. In addition, EPO significantly enhanced phosphorylation of Smad2 and Smad3 in fibroblasts and also elevated phosphorylation of Smad3 in wound tissue. Blockade of TGF-b using a neutralizing anti-TGF-b antibody attenuated EPO-induced acceleration of wound epithelialization in vivo and markedly reversed EPO effects on mRNA expression of TGF-b1 and a-SMA. In conclusion, EPO caused activation of the Smad-dependent TGF-b signaling pathway, enhanced differentiation of myofibroblasts, and accelerated skin wound closure.

BNIP3 induction by hypoxia stimulates FASN-dependent free fatty acid production enhancing therapeutic potential of umbilical cord blood-derived human mesenchymal stem cells

“…Furthermore, we present in vivo evidence that BNIP3-induced UCB-hMSCs transplantation by hypoxia pretreatment or PA accelerates myoblast switch and blood vessel formation, as well as the skin wound healing process. A phenotypic switch of fibroblasts toward myofibroblasts via myofibroblast development has been reported as a representative characteristic of wound repair and maturation [80], [81]. Although transplanted UCB-hMSCs at the wound site are exposed to hypoxia, due to low density of vascular distribution, BNIP3 silencing of UCB-hMSCs with normoxia pretreatment did not significantly affect this process.…”

Topical application of Acalypha indica accelerates rat cutaneous wound healing by up-regulating the expression of Type I and III collagen

“…The increased levels of TGF-b1 in Acalypha indica treated rats substantiate the results of Atiba et al (2011) in which they have used Aloe vera and found increased healing through enhanced expression of TGF-b1. Siebert et al (2011) have reported that erythropoietin accelerates wound closure by activating the TGF-b signaling pathway which is responsible for enhanced differentiation of myofibroblasts. Aloe vera was found to augment and accelerate acute radiation-delayed wound healing by increasing the expression of TGF-b1 (Atiba et al, 2011).…”

TGF-β/Smad signaling through DOCK4 facilitates lung adenocarcinoma metastasis

“…To this end, we performed immunohistochemistry (IHC) on human lung ADC tissue microarrays (TMAs) using anti-DOCK4-specific and anti-p-Smad3-specific antibodies (Supplemental Fig. 2A; Siebert et al 2011). We observed that DOCK4 expression was significantly higher in tumor tissues compared with adjacent normal tissues (Supplemental Fig.…”