Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition
Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition
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DOI：
10.1073/pnas.1117988108
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发表时间：
2011-12-27
影响因子：
11.1
通讯作者：
Hogan, Brigid L. M.
中科院分区：
文献类型：
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作者：
Rock, Jason R.;Barkauskas, Christina E.;Hogan, Brigid L. M.
目前肺纤维化的治疗方案很少。创新可能来自对特征性纤维化病变细胞起源的更好理解。我们用共聚焦显微镜分析了正常和纤维化小鼠和人的肺，用几种常用的标记物来定义基质细胞群。在这两个物种中，我们观察到意想不到的基质细胞异质性。这些细胞包括许多具有周细胞分子和形态特征的细胞，它们是其他纤维化组织中肌成纤维细胞的来源。我们使用小鼠遗传工具跟踪博莱霉素诱导的肺纤维化模型中特定细胞类型的命运。利用可诱导的转基因等位基因对肺泡间质中的周细胞样细胞进行谱系追踪，我们发现该群体在纤维化区域增殖。然而，这些细胞及其后代都没有表达高水平的肌成纤维细胞标记α -平滑肌肌动蛋白（Acta2, aSMA）。然后，我们使用表面活性剂蛋白C-CreER（T2）敲入等位基因在体内跟踪II型肺泡细胞（AEC2）的命运。我们在细胞或分子水平上没有发现标记细胞从上皮细胞向间充质细胞转化为肌成纤维细胞的证据。相反，博莱霉素加速了先前报道的AEC2向AEC1细胞的转化。同样，带有Scgb1a1-CreER等位基因标记的上皮细胞不会产生成纤维细胞，但在博莱霉素诱导的肺损伤中产生AEC2和AEC1细胞。综上所述，我们的结果显示了以前未被认识到的纤维化病变中细胞类型增殖的异质性，并排除了周细胞和两种上皮细胞群作为肌成纤维细胞的起源。
There are currently few treatment options for pulmonary fibrosis. Innovations may come from a better understanding of the cellular origin of the characteristic fibrotic lesions. We have analyzed normal and fibrotic mouse and human lungs by confocal microscopy to define stromal cell populations with respect to several commonly used markers. In both species, we observed unexpected heterogeneity of stromal cells. These include numerous cells with molecular and morphological characteristics of pericytes, implicated as a source of myofibroblasts in other fibrotic tissues. We used mouse genetic tools to follow the fates of specific cell types in the bleomcyin-induced model of pulmonary fibrosis. Using inducible transgenic alleles to lineage trace pericyte-like cells in the alveolar interstitium, we show that this population proliferates in fibrotic regions. However, neither these cells nor their descendants express high levels of the myofibroblast marker alpha smooth muscle actin (Acta2, aSMA). We then used a Surfactant protein C-CreER(T2) knock-in allele to follow the fate of Type II alveolar cells (AEC2) in vivo. We find no evidence at the cellular or molecular level for epithelial to mesenchymal transition of labeled cells into myofibroblasts. Rather, bleomycin accelerates the previously reported conversion of AEC2 into AEC1 cells. Similarly, epithelial cells labeled with our Scgb1a1-CreER allele do not give rise to fibroblasts but generate both AEC2 and AEC1 cells in response to bleomycin-induced lung injury. Taken together, our results show a previously unappreciated heterogeneity of cell types proliferating in fibrotic lesions and exclude pericytes and two epithelial cell populations as the origin of myofibroblasts.