Expansion of hedgehog disrupts mesenchymal identity and induces emphysema phenotype
Chaoqun Wang, … , Harold A. Chapman, Tien Peng
Chaoqun Wang, … , Harold A. Chapman, Tien Peng
Published July 12, 2018
Citation Information: J Clin Invest. 2018;128(10):4343-4358. https://doi.org/10.1172/JCI99435.
View: Text | PDF
Research Article Development Pulmonology

Expansion of hedgehog disrupts mesenchymal identity and induces emphysema phenotype

Abstract

GWAS have repeatedly mapped susceptibility loci for emphysema to genes that modify hedgehog signaling, but the functional relevance of hedgehog signaling to this morbid disease remains unclear. In the current study, we identified a broad population of mesenchymal cells in the adult murine lung receptive to hedgehog signaling, characterized by higher activation of hedgehog surrounding the proximal airway relative to the distal alveoli. Single-cell RNA-sequencing showed that the hedgehog-receptive mesenchyme is composed of mostly fibroblasts with distinct proximal and distal subsets with discrete identities. Ectopic hedgehog activation in the distal fibroblasts promoted expression of proximal fibroblast markers and loss of distal alveoli and airspace enlargement of over 20% compared with controls. We found that hedgehog suppressed mesenchymal-derived mitogens enriched in distal fibroblasts that regulate alveolar stem cell regeneration and airspace size. Finally, single-cell analysis of the human lung mesenchyme showed that segregated proximal-distal identity with preferential hedgehog activation in the proximal fibroblasts was conserved between mice and humans. In conclusion, we showed that differential hedgehog activation segregates mesenchymal identities of distinct fibroblast subsets and that disruption of fibroblast identity can alter the alveolar stem cell niche, leading to emphysematous changes in the murine lung.

Authors

Chaoqun Wang, Nabora S. Reyes de Mochel, Stephanie A. Christenson, Monica Cassandras, Rebecca Moon, Alexis N. Brumwell, Lauren E. Byrnes, Alfred Li, Yasuyuki Yokosaki, Peiying Shan, Julie B. Sneddon, David Jablons, Patty J. Lee, Michael A. Matthay, Harold A. Chapman, Tien Peng

×

Figure 3

Expansion of Hh activation into the distal mesenchyme induces emphysematous changes.

Options: View larger image (or click on image) Download as PowerPoint
Expansion of Hh activation into the distal mesenchyme induces emphysemat...
(A) Expansion of Hh activation (Gli2creERT2-tdT/+:R26RYFP/SmoM2) into the distal alveoli–induced emphysematous changes in the alveolar airspace characterized by increase in mean chord length, enlarged alveolus size, and reduced density of alveoli in the distal compartment. (B) μCT of murine lungs demonstrates increased percentage of LAV as a ratio of the TLV in Hh-expanded mutants. Dark dots indicate airspace. (C) Leukocyte counts in BALF show that macrophage is the major composition of leukocytes and there is no significant difference in the number of leukocytes and macrophages of the BALF from both control and Hh-expanded mutants. (D) Distal mesenchyme–specific activation of Hh utilizing the PdgfracreERT2 allele phenocopied the Hh-expanded mutant (Gli2creERT2-tdT/+:R26RYFP/SmoM2). (E) Proximal mesenchyme-specific activation of Hh utilizing the Gli1creERT2 allele does not induce significant changes in the distal airspace morphology compared with controls. V, blood vessel. Data are represented as mean ± SEM, with n ≥ 4 per group. Statistical analysis was done using the 1-tailed Student’s t test. *P < 0.05. Scale bars: 100 μm (A, D, and E); 1 mm (B). Results were replicated (n ≥ 2 experiments).