Molecular insights using spatial transcriptomics of the distal lung in congenital diaphragmatic hernia.
Molecular insights using spatial transcriptomics of the distal lung in congenital diaphragmatic hernia.
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使用先天性膈疝远端肺空间转录组学的分子见解。
DOI：
10.1152/ajplung.00154.2023
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Keswani,SundeepG
中科院分区：
文献类型：
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作者：
Lingappan,Krithika;Olutoye2nd,OluyinkaO;Cantu,Abiud;CantuGutierrez,ManuelEliezer;Cortes-Santiago,Nahir;Hammond,JD;Gilley,Jamie;Quintero,JoselynRojas;Li,Hui;Polverino,Francesca;Gleghorn,JasonP;Keswani,SundeepG
先天性膈疝（CDH）肺血管发育和功能异常是导致肺动脉高压的重要因素。肺是一个非常异质的器官，具有明显的细胞多样性，对损伤和治疗剂的反应不同。空间转录组学提供了识别具有区域特异性的肺中这些不同细胞亚群的转录特征差异的无与伦比的能力。我们假设，与对照组（正常肺）相比，CDH肺的远端肺实质（选择作为感兴趣的区域）将显示出不同的转录组学特征。我们使用Nanostring GeoMx平台对来自男性和女性CDH以及对照新生儿的肺切片进行空间转录组学分析。人类CDH和对照肺的空间转录组学分析揭示了基因表达特征的关键差异。与CDH肺相比，对照肺中肺泡上皮相关基因（sftpa1和sftpc）和血管生成相关基因（epas1和fhl1）的表达增加。对照肺对维生素A的反应丰富，与CDH肺实质中凝血级联和nf - κ B介导的tnf - α信号异常相反。在男性CDH患者中，col1a1 （ECM重塑）和CD163表达较高。与CDH肺样本相比，对照肺样本中2型肺泡上皮细胞（AT-2）、动脉和肺毛细血管内皮细胞增加。据我们所知，这是首次在CDH患者中使用空间转录组学，确定了CDH病理生理中不同肺细胞亚群的贡献，并突出了性别特异性差异。这是首次在先天性膈疝（CDH）患者中使用空间转录组学，确定了不同肺细胞亚群在CDH病理生理中的作用，并强调了性别特异性差异。
Abnormal pulmonary vascular development and function in congenital diaphragmatic hernia (CDH) is a significant factor leading to pulmonary hypertension. The lung is a very heterogenous organ and has marked cellular diversity that is differentially responsive to injury and therapeutic agents. Spatial transcriptomics provides the unmatched capability of discerning the differences in the transcriptional signature of these distinct cell subpopulations in the lung with regional specificity. We hypothesized that the distal lung parenchyma (selected as a region of interest) would show a distinct transcriptomic profile in the CDH lung compared with control (normal lung). We subjected lung sections obtained from male and female CDH and control neonates to spatial transcriptomics using the Nanostring GeoMx platform. Spatial transcriptomic analysis of the human CDH and control lung revealed key differences in the gene expression signature. Increased expression of alveolar epithelial-related genes (SFTPA1andSFTPC) and angiogenesis-related genes (EPAS1andFHL1) was seen in control lungs compared with CDH lungs. Response to vitamin A was enriched in the control lungs as opposed to abnormality of the coagulation cascade and TNF-alpha signaling via NF-kappa B in the CDH lung parenchyma. In male patients with CDH, higher expression ofCOL1A1(ECM remodeling) and CD163 was seen. Increased type 2 alveolar epithelial cells (AT-2) and arterial and lung capillary endothelial cells were seen in control lung samples compared with CDH lung samples. To the best of our knowledge, this is the first use of spatial transcriptomics in patients with CDH that identifies the contribution of different lung cellular subpopulations in CDH pathophysiology and highlights sex-specific differences.NEW & NOTEWORTHYThis is the first use of spatial transcriptomics in patients with congenital diaphragmatic hernia (CDH) that identifies the contribution of different lung cellular subpopulations in CDH pathophysiology and highlights sex-specific differences.