Hedgehog Signaling Pathway Orchestrates Human Lung Branching Morphogenesis.
Hedgehog Signaling Pathway Orchestrates Human Lung Branching Morphogenesis.
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DOI：
10.3390/ijms23095265
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发表时间：
2022-05-09
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
Hedgehog（HH）信号通路在小鼠肺发育中起重要作用。我们推测HH通路是人类肺发育过程中分支所必需的，并且在肺发育不全中受损。分析单细胞、批量RNA测序数据和人胎儿肺组织以确定HH途径作用物的时空定位。在空气-液体界面中培养远端人肺段，并用SHH抑制剂（5E 1）处理，以确定HH抑制对体外人肺分支、上皮-间充质标志物和相关信号传导途径的影响。我们的研究结果表明，在人肺发育过程中，HH通路组分的早期和调节表达。抑制HH信号传导导致发育过程中分支减少以及上皮（SOX 2、SOX 9）和间充质（ACTA 2）祖细胞标志物失调。FGF和Wnt途径也在HH抑制后被破坏。最后，我们证明了HH信号元件在先天性腹股沟疝（CDH）患者的肺组织中下调。在这项研究中，我们第一次表明HH信号抑制改变了人类发育中肺的适当分支所需的重要基因和蛋白质。了解HH通路对人类肺部发育的作用可能会导致儿童肺部疾病的新治疗靶点的确定。
The Hedgehog (HH) signaling pathway plays an essential role in mouse lung development. We hypothesize that the HH pathway is necessary for branching during human lung development and is impaired in pulmonary hypoplasia. Single-cell, bulk RNA-sequencing data, and human fetal lung tissues were analyzed to determine the spatiotemporal localization of HH pathway actors. Distal human lung segments were cultured in an air-liquid interface and treated with an SHH inhibitor (5E1) to determine the effect of HH inhibition on human lung branching, epithelial-mesenchymal markers, and associated signaling pathways in vitro. Our results showed an early and regulated expression of HH pathway components during human lung development. Inhibiting HH signaling caused a reduction in branching during development and dysregulated epithelial (SOX2, SOX9) and mesenchymal (ACTA2) progenitor markers. FGF and Wnt pathways were also disrupted upon HH inhibition. Finally, we demonstrated that HH signaling elements were downregulated in lung tissues of patients with a congenital diaphragmatic hernia (CDH). In this study, we show for the first time that HH signaling inhibition alters important genes and proteins required for proper branching of the human developing lung. Understanding the role of the HH pathway on human lung development could lead to the identification of novel therapeutic targets for childhood pulmonary diseases.
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影响因子：
2.7
作者：
Fernandes-Silva H;Correia-Pinto J;Moura RS
通讯作者：
Moura RS
影响因子：
5.8
作者：
Ancel, Julien;Belgacemi, Randa;Dormoy, Valerian
通讯作者：
Dormoy, Valerian
影响因子：
11.1
作者：
Belgacemi, Randa;Luczka, Emilie;Dormoy, Valerian
通讯作者：
Dormoy, Valerian
DOI：
10.1002/path.5188
发表时间：
2019-03
期刊：
The Journal of pathology
影响因子：
--
作者：
Danopoulos S;Thornton ME;Grubbs BH;Frey MR;Warburton D;Bellusci S;Al Alam D
通讯作者：
Al Alam D
影响因子：
4.6
作者：
Bell, Sheila M.;Schreiner, Claire M.;Whitsett, Jeffrey A.
通讯作者：
Whitsett, Jeffrey A.