Basal epithelial stem cells cross an alarmin checkpoint for postviral lung disease

Wu, Kangyun; Kamimoto, Kenji; Zhang, Yong; Yang, Kuangying; Keeler, Shamus P.; Gerovac, Benjamin J.; Agapov, Eugene; Austin, Stephen P; Yantis, Jennifer; Gissy, Kelly A; Byers, Derek E.; Alexander‐Brett, Jennifer; Hoffmann, Christy; Wallace, Marianne; Hughes, Michael; Crouch, Erika C.; Morris, Samantha A.; Holtzman, Michael J.

doi:10.1172/jci149336

Cited by 38 publications

(70 citation statements)

References 69 publications

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“…Given that ΔNp63 deletion prior to injury prevents dysplastic repair from occurring while other studies deplete dysplastic cells after their injury-induced expansion, it is possible that the immune and fibrotic responses elicited in these distinct scenarios differ as well. Indeed, crosstalk between the dysplastic epithelium and the immune and mesenchymal responders to lung injury have been the focus of recent attention, and there is mounting evidence that Krt5 + cells can recruit pathological immune and mesenchymal subpopulations to the injured lung (Cassandras et al, 2020; Choi et al, 2020; Habermann et al, 2020; Kathiriya et al, 2022; Strunz et al, 2020; Wu et al, 2021). In light of this, absence of the dysplastic epithelium could impair recruitment of these pathologic, pro-fibrotic, and pro-inflammatory populations, which might in-and-of itself be beneficial to lung repair and allow other epithelial progenitors better able to respond to injury.…”

Section: Discussionmentioning

confidence: 99%

ΔNp63 drives dysplastic alveolar remodeling and restricts epithelial plasticity upon severe lung injury

Weiner

Zhao

Zayas

et al. 2022

Preprint

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Unlike many mammalian vital organs, the lung exhibits a robust, multifaceted regenerative response to severe injuries such as influenza infection, which primarily targets epithelial cells in the airways and alveoli. Quiescent lung-resident epithelial progenitors proliferate, migrate, and differentiate following lung injury, participating in two distinct reparative pathways: functionally beneficial regeneration and dysplastic tissue remodeling. Intrapulmonary airway-resident basal-like p63+ progenitors are one such progenitor cell type that migrates from the airways to form ectopic bronchiolar tissue in the alveoli, generating honeycomb-like cysts that fail to resolve after injury. Though this phenomenon is now well described, the cell-autonomous signals that drive dysplastic alveolar remodeling remain uncertain, a question made especially salient by observations that p63+ progenitors also expand dramatically upon diffuse alveolar damage in humans resulting from a variety of insults including SARS-CoV-2-induced ARDS. Here we show that the master basal cell transcription factor ΔNp63 is required for the immense migratory capacity of intrapulmonary p63+ progenitors and consequently for the dysplastic repair pathway manifest by these cells. We further demonstrate that ΔNp63 restricts the fate plasticity of intrapulmonary p63+ progenitors by regulating their epigenetic landscape, and that loss of ΔNp63 alters the deposition of active and repressive histone modifications at key differentiation gene loci, allowing ΔNp63KO progenitors to proceed towards airway or alveolar differentiation depending on their surrounding environment. These insights into the regulatory mechanisms of dysplastic repair and intrapulmonary p63+ progenitor fate choice highlight potential therapeutic targets to promote more effective alveolar regeneration following severe lung injuries.

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Section: Discussionmentioning

confidence: 99%

ΔNp63 drives dysplastic alveolar remodeling and restricts epithelial plasticity upon severe lung injury

Weiner

Zhao

Zayas

et al. 2022

Preprint

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“…Images were captured using the Nanozoomer (Hamamatsu) at the Alafi Neuroimaging Core at Washington University. Hematoxylin + area as an index of cellularity was quantified in whole lung sections using a NanoZoomer slide scanner (Hamamatsu) and ImageJ software as described previously (Wu et al, 2021).…”

Section: Lung Histologymentioning

confidence: 99%

Nasally delivered interferon-λ protects mice against infection by SARS-CoV-2 variants including Omicron

et al. 2022

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“…Notably, among the 3 studied COVID-19 lungs, the one with morphologically defined microcysts (UNC#3) contained epithelial cells with expression of aberrant basaloid gene features (Supplementary Figure 3D) (29), suggesting the addition of an IPF-like pathophysiology to a post-viral muco-regulatory epithelial dysfunction, i.e., bronchiolization of "microcysts", which may resemble the features observed during lung repair after influenza or parainfluenza virus infection in mice (30)(31)(32)(33). Spatial transcriptomic analyses of grouped COVID-19 bronchioles provided confirmatory evidence for upregulation of mucin-associated pathways, coupled to upregulated host defense response and remodeling pathways, whereas cilium assembly pathways were downregulated (Supplementary Figure 4).…”

Section: Spatial Transcriptomic Studies Of Distal/terminal Bronchiole...mentioning

confidence: 93%

Prevalence and Mechanisms of Mucus Accumulation in COVID-19 Lung Disease

Kato

Asakura

Edwards³

et al. 2022

Am J Respir Crit Care Med

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SHR provided primary human bronchial epithelial (HBE) cells and excised lungs. KO and FBA provided human control lung sections. LBT, ACB, SS, FJM, SMH, DSC, and NIHCAC provided COVID-19 autopsy lung sections. TK, TA, and PH reviewed these sections. CEE, MRC and ABB performed in vitro SARS-CoV-2 infection to HBE cell cultures and virus titering. HD and YM contributed to bioinformatic and statistical analysis. RCG performed RNA in situ hybridization. LS performed western blotting. TK, TA and YM quantified the images. TK and TA performed all the other experiments. CE provided mouse anti-MUC5B antibody. GDC supervised the GeoMx assays. GC and WKO provided guidance and feedback to the overall work. WKO, SHR, RSB, and RCB designed and supervised the project. TK and TA drafted the

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Basal epithelial stem cells cross an alarmin checkpoint for postviral lung disease

Abstract: Conflict of interest statement: MJH is founder and equity-holder in NuPeak Therapeutics Inc and is a member of the Data Safety Monitoring Board for AstraZeneca. KW, YZ, SPK, BJG, and MJH are inventors on patents for mitogen-activated protein kinase (MAPK) inhibitors and uses thereof.

Cited by 38 publications

References 69 publications

ΔNp63 drives dysplastic alveolar remodeling and restricts epithelial plasticity upon severe lung injury

ΔNp63 drives dysplastic alveolar remodeling and restricts epithelial plasticity upon severe lung injury

Nasally delivered interferon-λ protects mice against infection by SARS-CoV-2 variants including Omicron

Prevalence and Mechanisms of Mucus Accumulation in COVID-19 Lung Disease

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