Glucocorticoid regulates mesenchymal cell differentiation required for perinatal lung morphogenesis and function

Author:

Bridges James P.12,Sudha Parvathi1,Lipps Dakota3,Wagner Andrew3,Guo Minzhe1,Du Yina1ORCID,Brown Kari1,Filuta Alyssa1,Kitzmiller Joseph1,Stockman Courtney1,Chen Xiaoting4,Weirauch Matthew T.2546,Jobe Alan H.12,Whitsett Jeffrey A.12,Xu Yan125ORCID

Affiliation:

1. Perinatal Institute, Section of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

2. Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio

3. College of Engineering and Applied Science, University of Cincinnati, Cincinnati, Ohio

4. Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

5. Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

6. Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

Abstract

While antenatal glucocorticoids are widely used to enhance lung function in preterm infants, cellular and molecular mechanisms by which glucocorticoid receptor (GR) signaling influences lung maturation remain poorly understood. Deletion of the glucocorticoid receptor gene ( Nr3c1) from fetal pulmonary mesenchymal cells phenocopied defects caused by global Nr3c1 deletion, while lung epithelial- or endothelial-specific Nr3c1 deletion did not impair lung function at birth. We integrated genome-wide gene expression profiling, ATAC-seq, and single cell RNA-seq data in mice in which GR was deleted or activated to identify the cellular and molecular mechanisms by which glucocorticoids control prenatal lung maturation. GR enhanced differentiation of a newly defined proliferative mesenchymal progenitor cell (PMP) into matrix fibroblasts (MFBs), in part by directly activating extracellular matrix-associated target genes, including Fn1, Col16a4, and Eln and by modulating VEGF, JAK-STAT, and WNT signaling. Loss of mesenchymal GR signaling blocked fibroblast progenitor differentiation into mature MFBs, which in turn increased proliferation of SOX9+ alveolar epithelial progenitor cells and inhibited differentiation of mature alveolar type II (AT2) and AT1 cells. GR signaling controls genes required for differentiation of a subset of proliferative mesenchymal progenitors into matrix fibroblasts, in turn, regulating signals controlling AT2/AT1 progenitor cell proliferation and differentiation and identifying cells and processes by which glucocorticoid signaling regulates fetal lung maturation.

Funder

CCHMC GAP

HHS | NIH | National Heart, Lung, and Blood Institute

Publisher

American Physiological Society

Subject

Cell Biology,Physiology (medical),Pulmonary and Respiratory Medicine,Physiology

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