Publication Date
10-1-2023
Journal
American Journal of Physiology-Lung Cellular and Molecular Physiology
DOI
10.1152/ajplung.00154.2023
PMID
37605849
PMCID
PMC10639013
PubMedCentral® Posted Date
4-22-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Infant, Newborn, Humans, Male, Female, Hernias, Diaphragmatic, Congenital, Transcriptome, Endothelial Cells, Lung, Hypertension, Pulmonary, Phenyl Ethers, Muscle Proteins, Intracellular Signaling Peptides and Proteins, LIM Domain Proteins
Abstract
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 (SFTPA1 and SFTPC) and angiogenesis-related genes (EPAS1 and FHL1) 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 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 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 & NOTEWORTHY This 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.
Graphical Abstract
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Critical Care Commons, Internal Medicine Commons, Medical Sciences Commons, Oncology Commons, Pulmonology Commons, Sleep Medicine Commons
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