Transforming Growth Factor-β Receptor-Mediated, p38 Mitogen-Activated Protein Kinase-Dependent Signaling Drives Enhanced Myofibroblast Differentiation during Skin Wound Healing in Mice Lacking Hyaluronan Synthases 1 and 3.
Transforming Growth Factor-β Receptor-Mediated, p38 Mitogen-Activated Protein Kinase-Dependent Signaling Drives Enhanced Myofibroblast Differentiation during Skin Wound Healing in Mice Lacking Hyaluronan Synthases 1 and 3.
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转化生长因子-β 受体介导的 p38 丝裂原激活蛋白激酶依赖性信号传导在缺乏透明质酸合成酶 1 和 3 的小鼠皮肤伤口愈合过程中增强肌成纤维细胞分化。
DOI：
10.1016/j.ajpath.2022.08.003
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Maytin,EdwardV
中科院分区：
文献类型：
--
作者：
Wang,Yan;Mack,JudithA;Hascall,VincentC;Maytin,EdwardV
正常的肌成纤维细胞分化对皮肤伤口的正常愈合至关重要。肌成纤维细胞分化的标志物α-平滑肌肌动蛋白(α-SMA)的新表达是由转化生长因子-β受体介导的信号传导驱动的。透明质酸及其三种合成酶--透明质酸合成酶(有1、2和3)也参与了这一过程。在Has1/3双基因敲除(Has1/3-空)小鼠中，皮肤伤口的愈合速度显著加快。在此情况下，转化生长因子-β活性和真皮胶原成熟增加在1/3缺失愈合皮肤。与野生型成纤维细胞相比，从has1/3基因缺失小鼠分离的原代皮肤成纤维细胞具有更高的转化生长因子-β活性、α-SMA表达和p38丝裂原活化蛋白激酶的磷酸化水平。P38α丝裂原活化蛋白激酶是HAS1/3缺失的成纤维细胞中非规范的β受体信号通路中的必需元件，该信号通路驱动α-SMA的表达。Myocardin相关转录因子(MRTF)是一种与转录因子血清反应因子(SRF)结合的辅因子，也是关键因素。在Has1/3缺失的成纤维细胞中，MRTF的核定位增加，与SRF的结合增强。通过RNA干扰抑制mrtf或srf的表达可抑制α-SMA在基础水平的表达，并减少其在HAS1/3缺失的成纤维细胞中的过度表达。有趣的是，在HAS1/3基因缺失小鼠的愈合皮肤和成纤维细胞中，总基质金属蛋白酶活性增加，这可能解释了转化生长因子-β活性增加的原因。
Normal myofibroblast differentiation is critical for proper skin wound healing. Neoexpression of α-smooth muscle actin (α-SMA), a marker for myofibroblast differentiation, is driven by transforming growth factor (TGF)-β receptor–mediated signaling. Hyaluronan and its three synthesizing enzymes, hyaluronan synthases (Has 1, 2, and 3), also participate in this process. Closure of skin wounds is significantly accelerated in Has1/3 double-knockout (Has1/3-null) mice. Herein, TGF-β activity and dermal collagen maturation were increased in Has1/3-null healing skin. Cultures of primary skin fibroblasts isolated from Has1/3-null mice had higher levels of TGF-β activity, α-SMA expression, and phosphorylation of p38 mitogen-activated protein kinase at Thr180/Tyr182, compared with wild-type fibroblasts. p38α mitogen-activated protein kinase was a necessary element in a noncanonical TGF-β receptor signaling pathway driving α-SMA expression in Has1/3-null fibroblasts. Myocardin-related transcription factor (MRTF), a cofactor that binds to the transcription factor serum response factor (SRF), was also critical. Nuclear localization of MRTF was increased, and MRTF binding to SRF was enhanced in Has1/3-null fibroblasts. Inhibition of MRTF or SRF expression by RNA interference suppresses α-SMA expression at baseline and diminished its overexpression in Has1/3-null fibroblasts. Interestingly, total matrix metalloproteinase activity was increased in healing skin and fibroblasts from Has1/3-null mice, possibly explaining the increased TGF-β activation.