Dermal Transforming Growth Factor-β Responsiveness Mediates Wound Contraction and Epithelial Closure
Dermal Transforming Growth Factor-β Responsiveness Mediates Wound Contraction and Epithelial Closure
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DOI：
10.2353/ajpath.2010.090283
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发表时间：
2010-01-01
影响因子：
6
通讯作者：
Bhowmick, Neil A.
中科院分区：
文献类型：
--
作者：
Martinez-Ferrer, Magaly;Afshar-Sherif, Ali-Reza;Bhowmick, Neil A.
基质-上皮相互作用在伤口愈合过程中很重要。伤口部位的转化生长因子-β (TGF-β) 信号传导与上皮再形成、炎症浸润、伤口收缩以及细胞外基质沉积和重塑有关。最终，TGF-β 是真皮疤痕形成的核心。由于无疤痕胚胎伤口与真皮 TGF-β 信号传导的缺乏有关，因此我们通过开发一种新型、可诱导、有条件的成纤维细胞 TGF-β II 型受体敲除 (Tgfbr2(dermalKO)) 小鼠模型，专门研究了 TGF-β 信号传导在真皮成纤维细胞中的作用。在对照和 Tgfbr2(dermaIKO) 背部皮肤中研究全层切除伤口。与对照组相比，Tgfbr2(dermalKO) 伤口加速了上皮再生和闭合，在愈合后 4 天内重新出现。真皮中 TGF-β 信号传导的丧失导致胶原蛋白沉积和重塑减少，与伤口收缩程度减少和巨噬细胞浸润增加相关。 Tgfbr2(dermalKO) 和对照皮肤具有相似数量的肌成纤维细胞，表明肌成纤维细胞分化并不是伤口收缩减少的原因。然而，Tgfbr2（dermalKO）成纤维细胞中细胞-基质相互作用的几种介质减少，包括α1、α2和β1整合素，并且胶原凝胶收缩减弱。血管舒张剂刺激的含磷蛋白的板状伪足的肌动蛋白细胞骨架组织存在相关缺陷。这项研究表明，旁分泌和自分泌 TGF-β 真皮信号传导机制介导巨噬细胞募集、上皮再生和伤口收缩。 (Am J Pathol 2010, 176:98-107; DOI: 10.2353/ajpath.2010.090283)
Stromal-epithelial interactions are important during wound healing. Transforming growth factor-beta (TGF-beta) signaling at the wound site has been implicated in re-epithelization, inflammatory infiltration, wound contraction, and extracellular matrix deposition and remodeling. Ultimately, TGF-beta is central to dermal scarring. Because scarless embryonic wounds are associated with the lack of dermal TGF-beta signaling, we studied the role of TGF-beta signaling specifically in dermal fibroblasts through the development of a novel, inducible, conditional, and fibroblastic TGF-beta type II receptor knockout (Tgfbr2(dermalKO)) mouse model. Full thickness excisional wounds were studied in control and Tgfbr2(dermaIKO) back skin. The Tgfbr2(dermalKO) wounds had accelerated re-epithelization and closure compared with controls, resurfacing within 4 days of healing. The loss of TGF-beta signaling in the dermis resulted in reduced collagen deposition and remodeling associated with a reduced extent of wound contraction and elevated macrophage infiltration. Tgfbr2(dermalKO) and control skin had similar numbers of myofibroblastic cells, suggesting that myofibroblastic differentiation was not responsible for reduced wound contraction. However, several mediators of cell-matrix interaction were reduced in the Tgfbr2(dermalKO) fibroblasts, including alpha 1, alpha 2, and beta 1 integrins, and collagen gel contraction was diminished. There were associated deficiencies in actin cytoskeletal organization of vasodilator-stimulated phosphoprotein-containing lamellipodia. This study indicated that paracrine and autocrine TGF-beta dermal signaling mechanisms mediate macrophage recruitment, re-epithelization, and wound contraction. (Am J Pathol 2010, 176:98-107; DOI: 10.2353/ajpath.2010.090283)