Lineage-negative Progenitors Mobilize to Regenerate Lung Epithelium after Major Injury
By A. Vaughan, A. Brumwell, Ying Xi, J. Gotts, D. Brownfield, B. Treutlein, Kevin Tan, Victor Tan, Fengchun Liu, M. Looney and 3 more. Nature, 2014
628 citations recorded by the source corpus.
Broadly, tissue regeneration is achieved in two ways: by proliferation of common differentiated cells and/or by deployment of specialized stem/progenitor cells. Which of these pathways applies is both organ- and injury-specific. Current models in the lung posit that epithelial repair can be attributed to cells expressing mature lineage markers. By contrast, here we define the regenerative role of previously uncharacterized, rare lineage-negative epithelial stem/progenitor (LNEP) cells present within normal distal lung. Quiescent LNEPs activate a ΔNp63 (a p63 splice variant) and cytokeratin 5 remodelling program after influenza or bleomycin injury in mice. Activated cells proliferate and migrate widely to occupy heavily injured areas depleted of mature lineages, at which point they differentiate towards mature epithelium. Lineage tracing revealed scant contribution of pre-existing mature epithelial cells in such repair, whereas orthotopic transplantation of LNEPs, isolated by a definitive surface profile identified through single-cell sequencing, directly demonstrated the proliferative capacity and multipotency of this population. LNEPs require Notch signalling to activate the ΔNp63 and cytokeratin 5 program, and subsequent Notch blockade promotes an alveolar cell fate. Persistent Notch signalling after injury led to parenchymal ‘micro-honeycombing’ (alveolar cysts), indicative of failed regeneration. Lungs from patients with fibrosis show analogous honeycomb cysts with evidence of hyperactive Notch signalling. Our findings indicate that distinct stem/progenitor cell pools repopulate injured tissue depending on the extent of the injury, and the outcomes of regeneration or fibrosis may depend in part on the dynamics of LNEP Notch signalling.
Subfields: Pulmonary and Respiratory Medicine, Surgery
View Paper: https://www.semanticscholar.org/paper/f2541fe2486083c380221915220b1f22838af183
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In Pulmonary and Respiratory Medicine
Citations in the corpus
- Single-cell RNA sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis (2019, background): “Furthermore, the cytokeratin profile of this KRT5−/KRT17+ niche appears distinct from that characterizing “lineage-negative epithelial progenitor” cells previously described in mouse models (46, 47).”
- TGF-β1 Signaling and Tissue Fibrosis. (2018, background): “…overly sensitive because of weak and transient activation of the cell-specific promoter in offtarget cells leading to sufficient expression of Cre recombinase to permanently activate reporter gene expression, thus potentially confusing the cellular origin of the labeled cell (Vaughan et al. 2015).”
- Acute Respiratory Distress Syndrome (2017, background): “blasts and the formation of a provisional matrix, as well as proliferation of airway progenitor cells and type II alveolar epithelial cells (AECII), with differentiation into type I alveolar epithelial cells (AECI).(28) During the fibrotic phase of ARDS (Panel B), which is strongly”