PDF(Pubmed)
Abstract：
Re-epithelialization is an important step in skin wound healing, referring to the migration, proliferation, and differentiation of keratinocytes around the wound. During this process, the edges of the wound begin to form new epithelial cells, which migrate from the periphery of the wound towards the center, gradually covering the entire wound area. These newly formed epithelial cells proliferate and differentiate, ultimately forming a protective layer over the exposed dermal surface. Wound endogenous electric fields (EFs) are known as the dominant factor to facilitate the epidermal migration to wound center. However, the precise mechanisms by which EFs promote epidermal migration remains elusive. Here, we found that in a model of cultured keratinocyte monolayer in vitro, EFs application reversed the differentiation of cells, as indicated by the reduction of the early differentiation markers K1 and K10. Genetic manipulation confirmed that EFs reversed keratinocyte differentiation through down-regulating the E-cadherin-mediated adhesion. By RNA-sequencing analysis, we screened out Snail as the transcription suppressor of E-cadherin. Snail knockdown abolished the down-regulation of E-cadherin and the reversal of differentiation induced by EFs. KEGG analysis identified PI3K/AKT signaling for Snail induction under EFs. Inhibition of PI3K by LY294002 diminished the EFs-induced AKT activation and Snail augmentation, largely restoring the level of E-cadherin reduced by EFs. Finally, in model of full-thickness skin wounds in pigs, we found that weakening of the wound endogenous EFs by the direction-reversed exogenous EFs resulted in an up-regulation of E-cadherin and earlier differentiation in newly formed epidermis in vivo. Our research suggests that electric fields (EFs) decrease E-cadherin expression by suppressing the PI3K/AKT/Snail pathway, thereby reversing the differentiation of keratinocytes. This discovery provides us with new insights into the role of electric fields in wound healing. EFs intervene in intracellular signaling pathways, inhibiting the expression of E-cadherin, which results in a lower differentiation state of keratinocytes. In this state, keratinocytes exhibit increased migratory capacity, facilitating the migration of epidermal cells and wound reepithelialization.
摘要：
再上皮化是皮肤伤口愈合的重要步骤，提到迁移，扩散,和伤口周围角质形成细胞的分化。在这个过程中,伤口的边缘开始形成新的上皮细胞，从伤口的外围向中心迁移，逐渐覆盖整个伤口区域。这些新形成的上皮细胞增殖和分化，最终在暴露的皮肤表面上形成保护层。已知伤口内源性电场(EF)是促进表皮向伤口中心迁移的主要因素。然而,EF促进表皮迁移的确切机制仍然难以捉摸。这里,我们发现在体外培养的角质形成细胞单层模型中，EF的应用逆转了细胞的分化，如早期分化标记K1和K10的减少所示。遗传操作证实，EF通过下调E-cadherin介导的粘附来逆转角质形成细胞的分化。通过RNA测序分析,我们筛选出蜗牛作为E-cadherin的转录抑制因子。蜗牛敲除消除了E-cadherin的下调和EF诱导的分化逆转。KEGG分析鉴定了EF下蜗牛诱导的PI3K/AKT信号传导。LY294002对PI3K的抑制作用减少了EF诱导的AKT激活和蜗牛增强，很大程度上恢复了EF降低的E-cadherin水平。最后,在猪全层皮肤伤口模型中，我们发现，方向逆转的外源性EF削弱了伤口内源性EF，导致E-cadherin上调，并在体内新形成的表皮中早期分化。我们的研究表明，电场（EF）通过抑制PI3K/AKT/Snail途径降低E-cadherin的表达，从而逆转角质形成细胞的分化。这一发现为我们提供了关于电场在伤口愈合中的作用的新见解。EF干预细胞内信号通路，抑制E-cadherin的表达，这导致角质形成细胞的较低分化状态。在这种状态下,角质形成细胞表现出增加的迁移能力，促进表皮细胞的迁移和伤口再上皮化。
