Ghatak, SubhadipKhanna, SavitaRoy, SashwatiThirunavukkarasu, MaheshPradeep, Seetur R.Wulff, Brian C.El Masry, Mohamed S.Sharma, AnuPalakurti, RavichandGhosh, NandiniXuan, YiWilgus, Traci A.Maulik, NilanjanaYoder, Mervin C.Sen, Chandan K.2024-06-122024-06-122023Ghatak S, Khanna S, Roy S, et al. Driving adult tissue repair via re-engagement of a pathway required for fetal healing. Mol Ther. 2023;31(2):454-470. doi:10.1016/j.ymthe.2022.09.002https://hdl.handle.net/1805/41450Fetal cutaneous wound closure and repair differ from that in adulthood. In this work, we identify an oxidant stress sensor protein, nonselenocysteine-containing phospholipid hydroperoxide glutathione peroxidase (NPGPx), that is abundantly expressed in normal fetal epidermis (and required for fetal wound closure), though not in adult epidermis, but is variably re-induced upon adult tissue wounding. NPGPx is a direct target of the miR-29 family. Following injury, abundance of miR-29 is lowered, permitting a prompt increase in NPGPx transcripts and protein expression in adult wound-edge tissue. NPGPx expression was required to mediate increased keratinocyte migration induced by miR-29 inhibition in vitro and in vivo. Increased NPGPx expression induced increased SOX2 expression and β-catenin nuclear localization in keratinocytes. Augmenting physiologic NPGPx expression via experimentally induced miR-29 suppression, using cutaneous tissue nanotransfection or targeted lipid nanoparticle delivery of anti-sense oligonucleotides, proved to be sufficient to overcome the deleterious effects of diabetes on this specific pathway to enhance tissue repair.en-USPublisher PolicymiR-29NPGPxEpidermal healingKeratinocyte migrationSkin barrier functionTissue nanotransfectionDiabetic wound healingEpidermal regenerationArticle