Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis
Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis
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DOI：
10.1172/jci94753
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发表时间：
2017-10-02
影响因子：
15.9
通讯作者：
Molkentin, Jeffery D.
中科院分区：
文献类型：
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作者：
Khalil, Hadi;Kanisicak, Onur;Molkentin, Jeffery D.
主细胞因子TGF-β介导与炎症和组织损伤相关的组织纤维化。TGF-β诱导成纤维细胞活化并分化为分泌细胞外基质蛋白的肌成纤维细胞。典型的TGF-β信号传导通过促进基因表达动员控制纤维化的Smad 2和Smad 3转录因子。然而，TGF-β-Smad 2/3信号在成纤维细胞介导的心脏纤维化中的重要性尚未在体内直接评估。在这里，我们研究了压力超负荷诱导的心脏纤维化的成纤维细胞和肌成纤维细胞特异性诱导Cre表达的小鼠系与选择性删除TGF-β受体Tgfbr 1/2，Smad 2，或Smad 3。成纤维细胞特异性缺失Tgfbr 1/2或Smad 3，而非Smad 2，显著降低压力超负荷诱导的纤维化反应以及由心脏特异性、抗潜伏期TGF-β突变转基因介导的纤维化。有趣的是，心脏成纤维细胞特异性缺失Tgfbr 1/2，而不是Smad 2/3，减弱了心脏对压力超负荷刺激的肥大反应。从机制上讲，从组织驻留成纤维细胞Smad 2/3的损失衰减心脏内损伤诱导的细胞扩张和纤维化介导基因的表达。从心脏成纤维细胞中删除Smad 2/3或Tgfbr 1/2类似地抑制了纤维化和细胞外基质重塑的基因程序，尽管Tgfbr 1/2的删除独特地改变了参与心肌细胞稳态和疾病补偿的一系列调控基因的表达。这些发现暗示TGF-β Smad 2/3信号在活化的组织驻留心脏成纤维细胞作为纤维化反应的主要介质。
The master cytokine TGF-beta mediates tissue fibrosis associated with inflammation and tissue injury. TGF-beta induces fibroblast activation and differentiation into myofibroblasts that secrete extracellular matrix proteins. Canonical TGF-beta signaling mobilizes Smad2 and Smad3 transcription factors that control fibrosis by promoting gene expression. However, the importance of TGF-beta-Smad2/3 signaling in fibroblast-mediated cardiac fibrosis has not been directly evaluated in vivo. Here, we examined pressure overload-induced cardiac fibrosis in fibroblast-and myofibroblast-specific inducible Cre-expressing mouse lines with selective deletion of the TGF-beta receptors Tgfbr1/2, Smad2, or Smad3. Fibroblast-specific deletion of Tgfbr1/2 or Smad3, but not Smad2, markedly reduced the pressure overload-induced fibrotic response as well as fibrosis mediated by a heart-specific, latency-resistant TGF-beta mutant transgene. Interestingly, cardiac fibroblast-specific deletion of Tgfbr1/2, but not Smad2/3, attenuated the cardiac hypertrophic response to pressure overload stimulation. Mechanistically, loss of Smad2/3 from tissue-resident fibroblasts attenuated injury-induced cellular expansion within the heart and the expression of fibrosis-mediating genes. Deletion of Smad2/3 or Tgfbr1/2 from cardiac fibroblasts similarly inhibited the gene program for fibrosis and extracellular matrix remodeling, although deletion of Tgfbr1/2 uniquely altered expression of an array of regulatory genes involved in cardiomyocyte homeostasis and disease compensation. These findings implicate TGF-beta Smad2/3 signaling in activated tissue-resident cardiac fibroblasts as principal mediators of the fibrotic response.