Fibrotic extracellular matrix activates a profibrotic positive feedback loop
Fibrotic extracellular matrix activates a profibrotic positive feedback loop
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DOI：
10.1172/jci71386
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发表时间：
2014-04-01
影响因子：
15.9
通讯作者：
Bitterman, Peter B.
中科院分区：
文献类型：
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作者：
Parker, Matthew W.;Rossi, Daniel;Bitterman, Peter B.
成纤维细胞对细胞外基质（ECM）的病理性重塑导致器官衰竭。特发性肺纤维化（IPF）的发展特征为肺中进行性纤维化瘢痕形成，最终导致窒息;然而，促进IPF的事件级联尚未明确定义。在这里，我们通过在来自IPF或对照患者的脱细胞肺ECM上培养从IPF患者肺组织或非纤维化肺组织产生的原代成纤维细胞来检查ECM和成纤维细胞之间的相互作用如何影响转录组和翻译组。令人惊讶的是，ECM的来源对基因表达的影响比细胞来源更大，并且翻译控制的差异比转录调控的改变更突出。引人注目的是，由IPF衍生的ECM诱导激活的基因富集了在IPF组织中检测到的编码ECM蛋白的基因。我们确定编码IPF相关ECM蛋白的基因是miR-29的靶点，miR-29在生长于IPF衍生ECM上的成纤维细胞中下调，并且ECM靶点的基线表达可以通过miR-29的过表达来恢复。我们的数据支持一个模型，在该模型中，成纤维细胞被激活，通过成纤维细胞和异常ECM之间的正反馈环病理性重塑IPF中的ECM。中断这种循环可能是IPF治疗的一种策略。
Pathological remodeling of the extracellular matrix (ECM) by fibroblasts leads to organ failure. Development of idiopathic pulmonary fibrosis (IPF) is characterized by a progressive fibrotic scarring in the lung that ultimately leads to asphyxiation; however, the cascade of events that promote IPF are not well defined.. Here, we examined how the interplay between the ECM and fibroblasts affects both the transcriptome and translatome by culturing primary fibroblasts generated from IPF patient lung tissue or nonfibrotic lung tissue on decellularized lung ECM from either IPF or control patients. Surprisingly, the origin of the ECM had a greater impact on gene expression than did cell origin, and differences in translational control were more prominent than alterations in transcriptional regulation. Strikingly, genes that were translationally activated by IPF-derived ECM were enriched for those encoding ECM proteins detected in IPF tissue. We determined that genes encoding IPF-associated ECM proteins are targets for miR-29, which was downregulated in fibroblasts grown on IPF-derived ECM, and baseline expression of ECM targets could be restored by overexpression of miR-29. Our data support a model in which fibroblasts are activated to pathologically remodel the ECM in IPF via a positive feedback loop between fibroblasts and aberrant ECM. Interrupting this loop may be a strategy for IPF treatment.