Platelet-derived growth factor-A and sonic hedgehog signaling direct lung fibroblast precursors during alveolar septal formation
Platelet-derived growth factor-A and sonic hedgehog signaling direct lung fibroblast precursors during alveolar septal formation
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DOI：
10.1152/ajplung.00011.2013
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发表时间：
2013-08-01
影响因子：
4.9
通讯作者：
McCoy, Diann M.
中科院分区：
文献类型：
--
作者：
McGowan, Stephen E.;McCoy, Diann M.
肺泡隔的形成对于支持生长中的哺乳动物的呼吸是必需的；在人类中，肺泡表面的消失和气体交换受损是肺气肿和肺纤维化的关键特征。血小板衍生生长因子 - A（PDGF - A）及其受体PDGF受体 - α（PDGFRα）在小鼠出生后第4天到第12天的次级隔伸长过程中是必需的，它们调节间质成纤维细胞的增殖和隔位置。我们研究了肺成纤维细胞（LF），以了解PDGFRα的表达是否能区分出一群具有增强增殖和迁移能力的前体细胞。我们鉴定出了一个表达音猬因子（Shh）和干细胞抗原 - 1（Sca1）的LF亚群。PDGF - A和Shh在体外都能增加细胞分裂和趋化性，但通过不同的机制。在原代LF培养物中，Shh仅通过涉及Rac1 - GTP产生的非经典途径发出信号，而Mlg新生小鼠LF细胞系则使用经典和非经典途径。LF在迁移过程中优先将其初级纤毛朝向其前端。此外，与其他肺泡细胞相比，在隔尖端更为丰富的表达PDGFRα的LF中，有更大比例的细胞具有初级纤毛。在肺气肿中，受损的肺泡隔无法再生，部分原因是细胞无法呈现出允许有效气体交换的结构。更好地理解LF在肺泡发育过程中的定位方式可以确定促进肺泡隔再生的信号通路。
Alveolar septal formation is required to support the respiration of growing mammals; in humans effacement of the alveolar surface and impaired gas exchange are critical features of emphysema and pulmonary fibrosis. Platelet-derived growth factor-A (PDGF-A) and its receptor PDGF-receptor-alpha (PDGFR alpha) are required for secondary septal elongation in mice during postnatal days 4 through 12 and they regulate the proliferation and septal location of interstitial fibroblasts. We examined lung fibroblasts (LF) to learn whether PDGFR alpha expression distinguished a population of precursor cells, with enhanced proliferative and migratory capabilities. We identified a subpopulation of LF that expresses sonic hedgehog (Shh) and stem cell antigen-1 (Sca1). PDGF-A and Shh both increased cytokinesis and chemotaxis in vitro, but through different mechanisms. In primary LF cultures, Shh signaled exclusively through a noncanonical pathway involving generation of Rac1-GTP, whereas both the canonical and noncanonical pathways were used by the Mlg neonatal mouse LF cell line. LF preferentially oriented their primary cilia toward their anterior pole during migration. Furthermore, a larger proportion of PDGFR alpha expressing LF, which are more abundant at the septal tips, bore primary cilia compared with other alveolar cells. In pulmonary emphysema, destroyed alveolar septa do not regenerate, in part because cells fail to assume a configuration that allows efficient gas exchange. Better understanding how LF are positioned during alveolar development could identify signaling pathways, which promote alveolar septal regeneration.