Research: Molecular insights using spatial transcriptomics of the distal lung in Congenital Diaphragmatic Hernia

Am J Physiol Lung Cell Mol Physiol

. 2023 Aug 22.

 doi: 10.1152/ajplung.00154.2023. Online ahead of print.

Molecular insights using spatial transcriptomics of the distal lung in Congenital Diaphragmatic Hernia

Krithika Lingappan 1Oluyinka O Olutoye 2nd 2Abiud Cantu 3Manuel Eliezer Cantu Gutierrez 3Nahir Cortes-Santiago 4J D Hammond 5Jamie Gilley 5Joselyn Rojas Quintero 6Hui Li 7Francesca Polverino 8Jason P Gleghorn 9Sundeep G Keswani 10

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Abnormal pulmonary vascular development and function in congenital diaphragmatic hernia (CDH) is a significant factor leading to pulmonary hypertension. The lung has marked cellular diversity that is differentially responsive to injury and therapeutic agents. Spatial transcriptomics provides 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 to 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 (SFTPA1, SFTPC) and angiogenesis related genes (EPAS1, FHL1) was seen in control lungs compared to 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 CDH patients, higher expression of COL1A1 (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 to CDH lung samples. To the best of our knowledge, this is the first use of spatial transcriptomics in CDH patients that identifies the contribution of different lung cellular sub-populations in CDH pathophysiology and highlights sex-specific differences.

Keywords: Congenital Diaphragmatic Hernia; Pulmonary Hypertension; Spatial Transcriptomics.

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