Keratinocyte migration is a mandatory aspect of wound healing. We have previously shown that amniotic membrane (AM) applied to chronic wounds assists healing through a process resulting in the overexpression of c‐Jun at the wound's leading edge. We have also demonstrated that AM modifies the genetic programme induced by transforming growth factor‐ß (TGF‐ß) in chronic wounds. Here we used a scratch assay of mink lung epithelial cells (Mv1Lu) and a spontaneously immortalized human keratinocyte cell line (HaCaT) cells to examine the influence of AM application on the underlying signalling during scratch closure. AM application induced c‐Jun phosphorylation at the leading edge of scratch wounds in a process dependent on MAPK and JNK signalling. Strikingly, when the TGF‐ß‐dependent Smad‐activation inhibitor SB431542 was used together with AM, migration improvement was partially restrained, whereas the addition of TGF‐ß had a synergistic effect on the AM‐induced cell migration. Moreover, antagonizing TGF‐ß with specific antibodies in both cell lines or knocking out TGF‐ß receptors in Mv1Lu cells had similar effects on cell migration as using SB431542. Furthermore, we found that AM was able to attenuate TGF‐ß‐Smad signalling specifically at the migrating edge; AM treatment abated Smad2 and Smad3 nuclear localization in response to TGF‐ß in a process dependent on mitogen‐activated protein kinase kinase 1 (MEK1) activation but independent of EGF receptor or JNK activation. The involvement of Smad signalling on AM effects on HaCaT keratinocytes was further corroborated by overexpression of either Smad2 or Smad3 and the use of Smad phosphorylation‐specific inhibitors, revealing a differential influence on AM‐induced migration for each Smad. Thus, AM TGF‐ß‐Smad signalling abating is essential for optimal cell migration and wound closure.
Journal of Tissue Engineering and Regenerative Medicine – Wiley
Published: Jan 1, 2018
Keywords: ; ; ; ; ;
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