Collagen VII plays a dual role in wound healing
Collagen VII plays a dual role in wound healing
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DOI：
10.1172/jci68127
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发表时间：
2013-08-01
影响因子：
15.9
通讯作者：
Bruckner-Tuderman, Leena
中科院分区：
文献类型：
--
作者：
Nystroem, Alexander;Velati, Daniela;Bruckner-Tuderman, Leena
虽然已知许多细胞内信号有助于伤口愈合，但细胞微环境在组织修复中的作用仍然难以捉摸。在这里，我们采用了2种不同的遗传性皮肤脆性小鼠模型，以评估基底膜蛋白胶原VII（COL 7A 1）在伤口愈合中的作用。COL 7A 1确保表皮与真皮的附着，并且其突变引起人类皮肤脆性疾病，称为隐性营养不良性大疱性表皮病（RDEB），其与恒定的伤口负担相关。我们表明，COL 7A 1是通过2个相互关联的机制对皮肤伤口闭合起作用的。首先，COL 7A 1是通过真皮-表皮交界处层粘连蛋白-332的组织化进行上皮再形成所必需的。其损失在伤口愈合期间扰乱层粘连蛋白-332组织，这反过来又消除了基底角质形成细胞中整合素α 6 β 4的严格极化表达，并对引导角质形成细胞迁移的层粘连蛋白-332/整合素α 6 β 4信号传导轴产生负面影响。其次，COL 7A 1支持真皮成纤维细胞迁移并调节肉芽组织中细胞因子的产生。这些在人类伤口中得到验证的发现将COL 7A 1确定为人类和小鼠生理伤口愈合的关键参与者，并且可能促进不仅针对RDEB而且针对其他慢性伤口的治疗策略的开发。
Although a host of intracellular signals is known to contribute to wound healing, the role of the cell microenvironment in tissue repair remains elusive. Here we employed 2 different mouse models of genetic skin fragility to assess the role of the basement membrane protein collagen VII (COL7A1) in wound healing. COL7A1 secures the attachment of the epidermis to the dermis, and its mutations cause a human skin fragility disorder coined recessive dystrophic epidermolysis bullosa (RDEB) that is associated with a constant wound burden. We show that COL7A1 is instrumental for skin wound closure by 2 interconnected mechanisms. First, COL7A1 was required for re-epithelialization through organization of laminin-332 at the dermal-epidermal junction. Its loss perturbs laminin-332 organization during wound healing, which in turn abrogates strictly polarized expression of integrin alpha 6 beta 4 in basal keratinocytes and negatively impacts the laminin-332/integrin alpha 6 beta 4 signaling axis guiding keratinocyte migration. Second, COL7A1 supported dermal fibroblast migration and regulates their cytokine production in the granulation tissue. These findings, which were validated in human wounds, identify COL7A1 as a critical player in physiological wound healing in humans and mice and may facilitate development of therapeutic strategies not only for RDEB, but also for other chronic wounds.