Gli1 + mesenchymal stromal cells form a pathological niche to promote airway progenitor metaplasia in the fibrotic lung

Aberrant epithelial reprogramming can induce metaplastic differentiation at sites of tissue injury that culminates in transformed barriers composed of scar and metaplastic epithelium. While the plasticity of epithelial stem cells is well characterized, the identity and role of the niche has not been...

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Published in:Nature cell biology Vol. 22; no. 11; pp. 1295 - 1306
Main Authors: Cassandras, Monica, Wang, Chaoqun, Kathiriya, Jaymin, Tsukui, Tatsuya, Matatia, Peri, Matthay, Michael, Wolters, Paul, Molofsky, Ari, Sheppard, Dean, Chapman, Hal, Peng, Tien
Format: Journal Article
Language:English
Published: England Nature Publishing Group 01.11.2020
Subjects:
Alveolar Epithelial Cells - metabolism
Alveolar Epithelial Cells - pathology
Alveoli
Animals
Basal cells
Bleomycin
Bone Morphogenetic Proteins - metabolism
Cell Differentiation
Cells, Cultured
Coculture Techniques
Disease Models, Animal
Epithelium
Fibrosis
Hedgehog protein
Hedgehog Proteins - metabolism
Keratin-5 - metabolism
Lung - metabolism
Lung - pathology
Lungs
Mesenchymal stem cells
Mesenchymal Stem Cells - metabolism
Mesenchymal Stem Cells - pathology
Mesenchyme
Metaplasia
Mice, Inbred C57BL
Mice, Knockout
Pulmonary Fibrosis - chemically induced
Pulmonary Fibrosis - genetics
Pulmonary Fibrosis - metabolism
Pulmonary Fibrosis - pathology
Respiratory tract
Scars
Signal Transduction
Signaling
Smoothened Receptor - metabolism
Stem Cell Niche
Stem cells
Stromal cells
Zinc Finger Protein GLI1 - genetics
Zinc Finger Protein GLI1 - metabolism
ISSN:1465-7392, 1476-4679, 1476-4679
Online Access:Get full text
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Summary:Aberrant epithelial reprogramming can induce metaplastic differentiation at sites of tissue injury that culminates in transformed barriers composed of scar and metaplastic epithelium. While the plasticity of epithelial stem cells is well characterized, the identity and role of the niche has not been delineated in metaplasia. Here, we show that Gli1 mesenchymal stromal cells (MSCs), previously shown to contribute to myofibroblasts during scarring, promote metaplastic differentiation of airway progenitors into KRT5 basal cells. During fibrotic repair, Gli1 MSCs integrate hedgehog activation signalling to upregulate BMP antagonism in the progenitor niche that promotes metaplasia. Restoring the balance towards BMP activation attenuated metaplastic KRT5 differentiation while promoting adaptive alveolar differentiation into SFTPC epithelium. Finally, fibrotic human lungs demonstrate altered BMP activation in the metaplastic epithelium. These findings show that Gli1 MSCs integrate hedgehog signalling as a rheostat to control BMP activation in the progenitor niche to determine regenerative outcome in fibrosis.
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ISSN:1465-7392
1476-4679
1476-4679
DOI:10.1038/s41556-020-00591-9