Agrin-Matrix Metalloproteinase-12 axis confers a mechanically competent microenvironment in skin wound healing.
Agrin-Matrix Metalloproteinase-12 axis confers a mechanically competent microenvironment in skin wound healing.
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DOI：
10.1038/s41467-021-26717-7
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发表时间：
2021-11-03
影响因子：
16.6
通讯作者：
Hong W
中科院分区：
文献类型：
--
作者：
Chakraborty S;Sampath D;Yu Lin MO;Bilton M;Huang CK;Nai MH;Njah K;Goy PA;Wang CC;Guccione E;Lim CT;Hong W
一个精心安排的伤口修复计划通过集体表皮细胞的增殖和迁移来推动皮肤修复。然而，支持伤口愈合的组织微环境的分子决定因素仍然知之甚少。在这里，我们发现蛋白多糖农业蛋白在早期的伤口微环境中是丰富的，是有效愈合所必需的。Agin通过增加角质形成细胞的硬度、牵引应力和流体速度场来增强其机械运作，以报复块状基质的刚性。重要的是，AGRIN通过增强肌球蛋白缆索，在损伤后感知几何应力和力，从而彻底改变了细胞骨架结构。此外，我们还发现基质金属蛋白酶-12(MMP12)是AGRIN机制的下游效应因子。我们还揭示了重组农业蛋白片段作为一种生物添加剂材料的前景，该材料通过参与MMP12促进伤口愈合来吸收最佳的机械生物学和促血管生成参数。综上所述，我们认为，AGRIN-MMP12途径整合了广泛的机械刺激，以协调一个有能力的皮肤创伤愈合利基。补充关键的细胞外基质(ECM)蛋白通过不清楚的机制促进伤口愈合。在这里，作者报告了损伤触发的Agin，一种ECM蛋白多糖，通过参与基质金属蛋白酶-12调节机械能力的利基，从而强制有效的皮肤伤口愈合。
An orchestrated wound healing program drives skin repair via collective epidermal cell proliferation and migration. However, the molecular determinants of the tissue microenvironment supporting wound healing remain poorly understood. Herein we discover that proteoglycan Agrin is enriched within the early wound-microenvironment and is indispensable for efficient healing. Agrin enhances the mechanoperception of keratinocytes by augmenting their stiffness, traction stress and fluidic velocity fields in retaliation to bulk substrate rigidity. Importantly, Agrin overhauls cytoskeletal architecture via enhancing actomyosin cables upon sensing geometric stress and force following an injury. Moreover, we identify Matrix Metalloproteinase-12 (MMP12) as a downstream effector of Agrin’s mechanoperception. We also reveal a promising potential of a recombinant Agrin fragment as a bio-additive material that assimilates optimal mechanobiological and pro-angiogenic parameters by engaging MMP12 in accelerated wound healing. Together, we propose that Agrin-MMP12 pathway integrates a broad range of mechanical stimuli to coordinate a competent skin wound healing niche. Replenishing key extracellular matrix (ECM) proteins facilitate wound healing through unclear mechanisms. Here the authors report that injury-triggered Agrin, an ECM proteoglycan, tunes a mechanocompetent niche by engaging MMP-12, thereby enforcing efficient skin wound healing.
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