Miao Qi, Ku Amy T, Nishino Yudai, Howard Jeffrey M, Rao Ajay S, Shaver Timothy M, Garcia Gloria E, Le Diep N, Karlin Kristen L, Westbrook Thomas F, Poli Valeria, Nguyen Hoang
Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, One Baylor Plaza, BCM 505, Houston, Texas 77030, USA.
1] Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, One Baylor Plaza, BCM 505, Houston, Texas 77030, USA [2] Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, One Baylor Plaza, BCM 505, Houston, Texas 77030, USA.
Nat Commun. 2014 Jun 9;5:4088. doi: 10.1038/ncomms5088.
Cell migration is an integral part of re-epithelialization during skin wound healing, a complex process involving molecular controls that are still largely unknown. Here we identify a novel role for Tcf3, an essential transcription factor regulating embryonic and adult skin stem cell functions, as a key effector of epidermal wound repair. We show that Tcf3 is upregulated in skin wounds and that Tcf3 overexpression accelerates keratinocyte migration and skin wound healing. We also identify Stat3 as an upstream regulator of Tcf3. We show that the promigration effects of Tcf3 are non-cell autonomous and occur independently of its ability to interact with β-catenin. Finally, we identify lipocalin-2 as the key secreted factor downstream of Tcf3 that promotes cell migration in vitro and wound healing in vivo. Our findings provide new insights into the molecular controls of wound-associated cell migration and identify potential therapeutic targets for the treatment of defective wound repair.
细胞迁移是皮肤伤口愈合过程中重新上皮化的一个重要组成部分，这是一个复杂的过程，涉及到分子调控，但目前在很大程度上仍不清楚。在这里，我们确定了Tcf3的一个新作用，Tcf3是一种调节胚胎和成年皮肤干细胞功能的重要转录因子，它是表皮伤口修复的关键效应因子。我们发现Tcf3在皮肤伤口中上调，并且Tcf3的过表达加速角质形成细胞迁移和皮肤伤口愈合。我们还确定Stat3是Tcf3的上游调节因子。我们表明，Tcf3的促迁移作用是非细胞自主性的，并且独立于其与β-连环蛋白相互作用的能力而发生。最后，我们确定lipocalin-2是Tcf3下游促进体外细胞迁移和体内伤口愈合的关键分泌因子。我们的研究结果为伤口相关细胞迁移的分子调控提供了新的见解，并确定了治疗有缺陷伤口修复的潜在治疗靶点。
