Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis
Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis
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DOI：
10.1073/pnas.1201840109
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发表时间：
2012-06-12
影响因子：
11.1
通讯作者：
Brenner, David A.
中科院分区：
文献类型：
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作者：
Kisseleva, Tatiana;Cong, Min;Brenner, David A.
肌成纤维细胞在肝纤维化中产生纤维性瘢痕。在四氯化碳（CCl 4）肝纤维化模型中，静止的肝星状细胞（HSC）被激活成为肌成纤维细胞。当去除潜在的病原体时，临床和实验性纤维化经历显著的消退，这些肌成纤维细胞完全消失。虽然一些肌成纤维细胞失活，但尚不清楚其他肌成纤维细胞是否会在纤维化消退期间恢复为无活性表型。我们使用基于Cre-LoxP的肌成纤维细胞遗传标记阐明了从CCl 4和酒精诱导的肝纤维化恢复过程中HSC/肌成纤维细胞的命运。在这里，我们证明了一半的肌成纤维细胞在肝纤维化消退过程中逃脱凋亡，下调纤维化基因，并获得类似于，但不同的表型，静止的HSC在他们的能力，更迅速地重新激活成肌成纤维细胞，以响应纤维化的刺激，并强烈地促进肝纤维化。HSC的失活与抗凋亡基因Hspa 1a/B的上调有关，Hspa 1a/B参与HSC在培养和体内的存活。
Myofibroblasts produce the fibrous scar in hepatic fibrosis. In the carbon tetrachloride (CCl4) model of liver fibrosis, quiescent hepatic stellate cells (HSC) are activated to become myofibroblasts. When the underlying etiological agent is removed, clinical and experimental fibrosis undergoes a remarkable regression with complete disappearance of these myofibroblasts. Although some myofibroblasts apoptose, it is unknown whether other myofibroblasts may revert to an inactive phenotype during regression of fibrosis. We elucidated the fate of HSCs/myofibroblasts during recovery from CCl4-and alcohol-induced liver fibrosis using Cre-LoxP-based genetic labeling of myofibroblasts. Here we demonstrate that half of the myofibroblasts escape apoptosis during regression of liver fibrosis, down-regulate fibrogenic genes, and acquire a phenotype similar to, but distinct from, quiescent HSCs in their ability to more rapidly reactivate into myofibroblasts in response to fibrogenic stimuli and strongly contribute to liver fibrosis. Inactivation of HSCs was associated with up-regulation of the anti-apoptotic genes Hspa1a/b, which participate in the survival of HSCs in culture and in vivo.