2017
DOI: 10.1038/ncb3580
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Local lung hypoxia determines epithelial fate decisions during alveolar regeneration

Abstract: SUMMARY After influenza infection, lineage-negative epithelial progenitors (LNEPs) exhibit a binary response to reconstitute epithelial barriers: activating a Notch-dependent ΔNp63/cytokeratin 5(Krt5) remodeling program or differentiating into alveolar type II cells (AEC2s). Here we show that local lung hypoxia, via hypoxia inducible factor (HIF1α), drives Notch signaling and Krt5pos basal-like cell expansion. Single cell transcriptional profiling of human AEC2s from fibrotic lungs revealed a hypoxic subpopula… Show more

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Cited by 230 publications
(267 citation statements)
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“…In Zone 4, Sftpc + and Krt5 + /Sftpc + cells are very rare (Extended Data Fig. 4I), confirming prior reports that the Krt5 + lineage cells do not efficiently regenerate Sftpc + cells 7 , except following forced Wnt activation 9 .…”
supporting
confidence: 86%
See 1 more Smart Citation
“…In Zone 4, Sftpc + and Krt5 + /Sftpc + cells are very rare (Extended Data Fig. 4I), confirming prior reports that the Krt5 + lineage cells do not efficiently regenerate Sftpc + cells 7 , except following forced Wnt activation 9 .…”
supporting
confidence: 86%
“…In contrast, Sox2-derived Krt5 + cells migrate from the proximal airway after acute lung injury, preventing loss of the epithelial barrier 69 . AEPs and Krt5 + cells likely act in concert, with Krt5 + cells acting rapidly to prevent immediate loss of epithelial barrier while AEPs simultaneously regenerate functional alveoli.…”
mentioning
confidence: 99%
“…Such alternative repair pathways are supported by several lines of evidence in the current and previous studies 3, 4 . First, transplantation of LNEPs into injured lungs leads to formation of either KRT5 cell clusters or AT2 cells, the latter of which are considered more important in gas exchange 3 .…”
supporting
confidence: 84%
“…One striking example is the formation of large clusters of keratin 5 (KRT5) cells that were originally discovered in a mouse model of severe influenza infection and also observed in fibrotic human lungs 2, 3 . Xi et al now considerably advance our understanding of the cellular origin and molecular regulation of these KRT5 cells 4 .…”
mentioning
confidence: 99%
“…Thus, it has been hypothesized that ΔNp63 + stem/progenitor cell mobilization contributes to alveolar type 2 cell regeneration after radiation injury (78). However, it is important to note that if there are hypoxic regions in injured lung then HIFα/ Notch signaling reprograms Δp63+/Krt5 + cells to form basal-like metaplasia (82). Additionally, an Nrf2 deficiency promotes radiation-induced alveolar type 2 cell epithelial-mesenchymal transitions into myofibroblasts (78).…”
Section: Nrf2 and Radiation-associated Pulmonary Injurymentioning
confidence: 99%