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.
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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

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Figure 4

Hh activation in distal mesenchyme reduces proliferation of alveolar stem cells.

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Hh activation in distal mesenchyme reduces proliferation of alveolar ste...
(A) Expansion of Hh into the distal mesenchyme reduced the number of SFTPC+ stem cells in the alveoli. (B–D) Expansion of Hh activation into the distal mesenchyme reduced BrdU incorporation into SFTPC+ alveolar stem cells during normal homeostasis (B) as well as after bleomycin-induced injury (C). Arrows indicate overlapping staining of SFTPC and BrdU. Statistical analysis of the percentage of BrdU-incorporated SFTPC+ cells (D). (E) tSNE plot demonstrates that Hgf is enriched in cluster 2 (bottom cluster), which marks the distal mesenchyme. In situ confirms expression of Hgf in the distal mesenchyme. (F) SFTPC+ alveolar stem cells express the HGF receptor, MET. Data are represented as mean ± SEM, with n ≥ 4 per group. Statistical analysis was done using 1-tailed Student’s t test. *P < 0.05. Scale bars: 100 μm. Results were replicated (n ≥ 2 experiments).