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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Vydané v:	Nature cell biology Ročník 22; číslo 11; s. 1295 - 1306
Hlavní autori:	Cassandras, Monica, Wang, Chaoqun, Kathiriya, Jaymin, Tsukui, Tatsuya, Matatia, Peri, Matthay, Michael, Wolters, Paul, Molofsky, Ari, Sheppard, Dean, Chapman, Hal, Peng, Tien
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	England Nature Publishing Group 01.11.2020
Predmet:	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
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1465-7392 1476-4679 1476-4679
DOI:	10.1038/s41556-020-00591-9