ArticleNature2015
Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury.
Article in Nature, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 457 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
457 citing papers in PubMed, 1 synthesis or guideline pooled it, 707 citations in OpenAlex.
- Lung Organoids: Systematic Review of Recent Advancements and its Future Perspectives.Tissue engineering and regenerative medicine · 2024Pooled it
- Autologous transplantation of P63Cell reports. Medicine · 2024Trial
- Article
- Functional Dissection of TP63 Dual-Promoter Regulatory Elements Reveals Context-Dependent Responsiveness to FOXA2, NKX2-1, SOX9, and TP63-Related Inputs.Current issues in molecular biology · 2026Article
- Transcriptomic signatures of IPF in ALI-cultured airway cells and their therapeutic implications.Thorax · 2026Article
- Activation of ERBB4 Pathway Inhibits Pathological Transdifferentiation of Lung Epithelial Progenitors into CD66cAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Influenza-induced tuft cell expansion is associated with changes in ILC2 populations in the distal lungs of mice.Physiological reports · 2026Article
- Ageing-associated regenerative failure in the lung: stem cell senescence and transitional cell persistence in idiopathic pulmonary fibrosis.European respiratory review : an official journal of the European Respiratory Society · 2026Review
- Epigenetic de-repression of basal cell metaplasia in aging AT2 cells is a risk factor for idiopathic pulmonary fibrosis (IPF).bioRxiv : the preprint server for biology · 2026Article
- Connexin 43 Loss in Endothelial Progenitors Facilitates Functional Airway Adaptation After Lung Injury.Research square · 2026Article
- Fibroblasts as regulators of lung immunity, repair and fibrosis.Nature reviews. Immunology · 2026Review
- Chronic TGFβ1 Signaling Drives Aberrant Alveolar-Basaloid Metaplasia through a KRT17-Stratifin migratory complex.bioRxiv : the preprint server for biology · 2026Article
- Influenza-induced tuft cell expansion alters ILC-mediated inflammation.bioRxiv : the preprint server for biology · 2026Article
- Unlocking Alveolar Regeneration: AT2 Stem Cells, Signaling Networks, and Therapeutic Frontiers.Stem cell reviews and reports · 2026Review
- Regenerative therapeutics for chronic obstructive pulmonary disease.Pharmacological reviews · 2026Review
- Advances in our understanding of distal progenitors in idiopathic pulmonary fibrosis: implications for novel therapeutics.The European respiratory journal · 2026Review
- Epithelial cells in chronic obstructive pulmonary disease exacerbations: Targets for lung repair.Pharmacological reviews · 2026Review
- Lung adventitial fibroblasts support type 2 Tregs to shape the response to influenza infection.bioRxiv : the preprint server for biology · 2026Article
- Dysplastic Epithelial Repair Propagates Chronic Pathology Through the Paracrine Transformation of Pulmonary Fibroblasts.bioRxiv : the preprint server for biology · 2026Article
- Hydrogel-Embedded Precision-Cut Lung Slices Recapitulate Fibrotic Gene Expression and Enable Therapeutic Response Evaluation.bioRxiv : the preprint server for biology · 2026Article
397 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.