Diversity of Interstitial Lung Fibroblasts Is Regulated by Platelet-Derived Growth Factor Receptor α Kinase Activity
Diversity of Interstitial Lung Fibroblasts Is Regulated by Platelet-Derived Growth Factor Receptor α Kinase Activity
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DOI：
10.1165/rcmb.2015-0095oc
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发表时间：
2016-04-01
影响因子：
6.4
通讯作者：
Perl，Anne-Karina T.
中科院分区：
文献类型：
--
作者：
Green，Jenna;Endale，Mehari;Perl，Anne-Karina T.
上皮-间充质细胞的相互作用和控制正常肺发育的因素是肺损伤、修复和纤维化的关键因素。许多研究已经调查了上皮祖细胞在肺再生过程中的作用和来源；然而，这些信息仅限于肺成纤维细胞。因此，了解成纤维细胞前体细胞的起源、表型和在肺发育、修复和再生中的作用有助于解决这些局限性。利用血小板衍生生长因子受体α-绿色荧光蛋白(PDGFRα-GFP)报告小鼠、基因芯片、实时聚合酶链式反应、流式细胞仪和免疫荧光技术，我们鉴定了两种不同的间质驻留成纤维细胞--肌成纤维细胞和基质成纤维细胞，并确定了PDGFRGFRα激酶活性在肺再生过程中调节其激活的作用。这两个群体的转录图谱显示了肌和基质成纤维细胞的基因特征。在肺泡再生过程中，观察到表达PDGFFRα的两个亚群的成纤维细胞在增殖、平滑肌肌动蛋白诱导和脂质含量方面的差异。虽然CD140α+CD2 9+细胞表现为肌成纤维细胞，但CD14 0α+CD34+细胞表现为基质和/或脂成纤维细胞。使用抑制剂尼洛替尼和显性活性的PDGFFRα-D842V突变后，PDGFFRαα的活性增加或丧失，表明PDGFRDNA在基质成纤维细胞分化中起重要作用。我们发现PDGFRα信号通过调节成纤维细胞的激活和基质成纤维细胞的分化来促进肺泡间隔的形成，而肌成纤维细胞的分化在很大程度上不依赖于PDGFRα。这些研究为肺部分切除术后再生过程中间质驻留成纤维细胞的表型和功能多样性以及分化的特异性程度提供了证据。
Epithelial–mesenchymal cell interactions and factors that control normal lung development are key players in lung injury, repair, and fibrosis. A number of studies have investigated the roles and sources of epithelial progenitors during lung regeneration; such information, however, is limited in lung fibroblasts. Thus, understanding the origin, phenotype, and roles of fibroblast progenitors in lung development, repair, and regeneration helps address these limitations. Using a combination of platelet-derived growth factor receptor α–green fluorescent protein (PDGFRα-GFP) reporter mice, microarray, real-time polymerase chain reaction, flow cytometry, and immunofluorescence, we characterized two distinct interstitial resident fibroblasts, myo- and matrix fibroblasts, and identified a role for PDGFRα kinase activity in regulating their activation during lung regeneration. Transcriptional profiling of the two populations revealed a myo- and matrix fibroblast gene signature. Differences in proliferation, smooth muscle actin induction, and lipid content in the two subpopulations of PDGFRα-expressing fibroblasts during alveolar regeneration were observed. Although CD140α+CD29+cells behaved as myofibroblasts, CD140α+CD34+appeared as matrix and/or lipofibroblasts. Gain or loss of PDGFRα kinase activity using the inhibitor nilotinib and a dominant-active PDGFRα-D842V mutation revealed that PDGFRα was important for matrix fibroblast differentiation. We demonstrated that PDGFRα signaling promotes alveolar septation by regulating fibroblast activation and matrix fibroblast differentiation, whereas myofibroblast differentiation was largely PDGFRα independent. These studies provide evidence for the phenotypic and functional diversity as well as the extent of specificity of interstitial resident fibroblasts differentiation during regeneration after partial pneumonectomy.