Age-dependent alveolar epithelial plasticity orchestrates lung homeostasis and regeneration

Penkala, Ian J.; Liberti, Derek C.; Pankin, J.; Sivakumar, Aravind; Kremp, Madison M.; Jayachandran, Sowmya; Katzen, Jeremy; Leach, John P.; Windmueller, Rebecca; Stolz, Katharine G.; Morley, Michael; Babu, Apoorva; Zhou, Shanshan; Frank, David B.; Morrisey, Edward E.

doi:10.1016/j.stem.2021.04.026

Cited by 95 publications

(106 citation statements)

References 73 publications

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“…These studies augment prior evidence that ECs can support epithelial repair 20,46 and patterning 47 via crosstalk with the mesenchyme. Our finding that tidal-level strain synergizes with Wnt/FGF withdrawal to induce AEC1 differentiation sheds additional light on previous observations that neither Wnt inhibition 45 nor genetic YAP activation in AEC2s (in effect, activating some of the downstream signaling induced by mechanical stretch, via molecular tools) 41,42 is sufficient to induce full differentiation to squamous AEC1s. It may be that local variation in strain levels within the alveolus 48 acts in tandem with short-range FB-derived Wnts 11 to determine epithelial differentiation state.…”

Section: Discussionsupporting

confidence: 76%

In vitro engineering of the lung alveolus

Leiby

Yuan

et al. 2022

Preprint

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Therapeutic lung regeneration is predicated upon successful reconstitution of lung alveoli, the functional units of gas exchange. Here, we identify requisite multimodal cues that are critical to reconstructing the alveolar epithelium and alveoli in lung scaffolds. Alveolar reconstruction in vitro is divided into several distinct phases. In the first phase, endothelial cells coordinate with fibroblasts and select exogenous factors to promote alveolar scaffold population with surfactant-secreting alveolar epithelial type 2 cells (AEC2s). After formation of organized epithelial alveolar-like structures, subsequent withdrawal of Wnt and FGF agonism synergizes with tidal-level mechanical strain to induce differentiation of AEC2s to squamous type 1 AECs (AEC1s) in cultured alveoli, in situ. These results outline a rational strategy to engineer an alveolus of AEC2s and AEC1s contained within epithelial-mesenchymal-endothelial units, and reveal the critical interplay amongst biochemical, cellular, and mechanical niche cues within the reconstituting alveolus.

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Section: Discussionsupporting

confidence: 76%

In vitro engineering of the lung alveolus

Leiby

Yuan

et al. 2022

Preprint

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“…For example, genetic ablation of basal cells in the trachea induces committed club cells to de-differentiate into basal cells, which can then respond to airway insults as endogenous basal cells would (Tata et al, 2013). Similarly, differentiated AT1s can assume progenitor functions with pneumonectomy injury, hyperoxic conditions in young mice, or Yap/Taz deletion and differentiate into AT2s (Jain et al, 2015; Penkala et al, 2021). In humans, this plasticity appears to be bidirectional, as AT2s can be driven to aberrantly transdifferentiate into basal cells when exposed to TGFβ signaling from altered CTHRC1 hi mesenchymal niche cells that arise in diseased lungs (Kathiriya et al, 2022).…”

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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“…Failure of Yap to undergo nuclear–cytoplasmic shuttling (i.e., sequestered in the nucleus) leads to the disorganization of the conducting airway epithelium without evidence of increased proliferation and with evidence of ectopic AT2 and AT1 cell markers ( 17 ). However, Yap has also been recently shown to mediate AT1-to-AT2 cell conversion with an important role in post-injury repair ( 29 ). Mst1 and Mst2 phosphorylate Yap, leading to cytoplasmic sequestration.…”

Section: Discussionmentioning

confidence: 99%

Fetal Tracheal Occlusion Increases Lung Basal Cells via Increased Yap Signaling

et al. 2022

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Fetal endoscopic tracheal occlusion (FETO) is an emerging surgical therapy for congenital diaphragmatic hernia (CDH). Ovine and rabbit data suggested altered lung epithelial cell populations after tracheal occlusion (TO) with transcriptomic signatures implicating basal cells. To test this hypothesis, we deconvolved mRNA sequencing (mRNA-seq) data and used quantitative image analysis in fetal rabbit lung TO, which had increased basal cells and reduced ciliated cells after TO. In a fetal mouse TO model, flow cytometry showed increased basal cells, and immunohistochemistry demonstrated basal cell extension to subpleural airways. Nuclear Yap, a known regulator of basal cell fate, was increased in TO lung, and Yap ablation on the lung epithelium abrogated TO-mediated basal cell expansion. mRNA-seq of TO lung showed increased activity of downstream Yap genes. Human lung specimens with congenital and fetal tracheal occlusion had clusters of subpleural basal cells that were not present in the control. TO increases lung epithelial cell nuclear Yap, leading to basal cell expansion.

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Age-dependent alveolar epithelial plasticity orchestrates lung homeostasis and regeneration

Cited by 95 publications

References 73 publications

In vitro engineering of the lung alveolus

In vitro engineering of the lung alveolus

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

Fetal Tracheal Occlusion Increases Lung Basal Cells via Increased Yap Signaling

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