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

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)- β 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- β 1 and of α -smooth muscle actin ( α -SMA) compared with non-wounded skin. EPO treatment accelerated wound epithelialization and induced mRNA expression of TGF- β 1 and α -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- β using a neutralizing anti-TGF- β antibody attenuated EPO-induced acceleration of wound epithelialization in vivo and markedly reversed EPO effects on mRNA expression of TGF- β 1 and α -SMA. In conclusion, EPO caused activation of the Smad-dependent TGF- β signaling pathway, enhanced differentiation of myofibroblasts, and accelerated skin wound closure.