Krithika Lingappan, Oluyinka O. Olutoye II, Abiud Cantu, Manuel Eliezer Cantu Gutierrez, Nahir Cortes-Santiago, J. D. Hammond, Jamie Gilley, Joselyn Rojas Quintero, Hui Li, Francesca Polverino, Jason P. Gleghorn, Sundeep G. Keswani
Children’s Hospital of Philadelphia. Baylor College of Medicine and Texas Children’s Hospital. University of Delaware.
United States
American Journal of Physiology Lung Cellular and Molecular Physiology
Am J Physiol Lung Cell Mol Physiol 2023;
DOI: 10.1152/ajplung.00154.2023
Abstract
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.
Category
Class III. Pulmonary Hypertension Associated with Lung Hypoplasia
Genetic Factors Associated with Pulmonary Vascular Disease
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
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