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

Nat Cell Biol. 2020 Nov;22(11):1295-1306. doi: 10.1038/s41556-020-00591-9. Epub 2020 Oct 12.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Epithelial Cells / metabolism*
  • Alveolar Epithelial Cells / pathology
  • Animals
  • Bleomycin
  • Bone Morphogenetic Proteins / metabolism*
  • Cell Differentiation*
  • Cells, Cultured
  • Coculture Techniques
  • Disease Models, Animal
  • Hedgehog Proteins / metabolism
  • Keratin-5 / metabolism
  • Lung / metabolism*
  • Lung / pathology
  • Mesenchymal Stem Cells / metabolism*
  • Mesenchymal Stem Cells / pathology
  • Metaplasia
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / pathology
  • Signal Transduction
  • Smoothened Receptor / metabolism
  • Stem Cell Niche*
  • Zinc Finger Protein GLI1 / genetics
  • Zinc Finger Protein GLI1 / metabolism*

Substances

  • Bone Morphogenetic Proteins
  • Gli1 protein, mouse
  • Hedgehog Proteins
  • Keratin-5
  • Shh protein, mouse
  • Smo protein, mouse
  • Smoothened Receptor
  • Zinc Finger Protein GLI1
  • Bleomycin