Indiana Center for Regenerative Medicine & Engineering, Indiana University Health Comprehensive Wound Center, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut Health, Farmington, CT 06030, USA.
Mol Ther. 2023 Feb 1;31(2):454-470. doi: 10.1016/j.ymthe.2022.09.002. Epub 2022 Sep 15.
Fetal 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.
胎儿皮肤伤口的闭合和修复与成人不同。在这项工作中，我们鉴定出一种氧化应激传感器蛋白，即非硒半胱氨酸磷脂氢过氧化物谷胱甘肽过氧化物酶（NPGPx），其在正常胎儿表皮中大量表达（并且是胎儿伤口闭合所必需的），但在成人表皮中不表达，但在成人组织受伤后可被不同程度地重新诱导。NPGPx 是 miR-29 家族的直接靶标。损伤后，miR-29 的丰度降低，允许 NPGPx 转录物和蛋白在成人伤口边缘组织中的快速增加。NPGPx 表达是介导 miR-29 抑制在体外和体内诱导的角质形成细胞迁移增加所必需的。增加的 NPGPx 表达诱导角质形成细胞中 SOX2 表达和 β-连环蛋白核定位增加。通过使用皮肤组织纳米转染或靶向脂质纳米颗粒递送来抑制 miR-29 以实验诱导生理性 NPGPx 表达，从而增加其表达，证明足以克服糖尿病对增强组织修复的这种特定途径的有害影响。
