TAZ is required for lung alveolar epithelial cell differentiation after injury

Sun, Tianhe; Huang, Zhiyu; Zhang, Hua; Posner, Clara; Jia, Guiquan; Ramalingam, Thirumalai R.; Xu, Min; Brightbill, Hans; Egen, Jackson G.; Dey, Anwesha; Arron, Joseph R.

doi:10.1172/jci.insight.128674

Cited by 67 publications

(64 citation statements)

References 52 publications

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“…Our results predict distinct transcriptional regulators as key switch points in terminal AT1 differentiation, including TAZ (Wwtr1), Sox4 and beta-catenin (Ctnnb1). The mechanistic importance of Wwtr1 (YAP/TAZ -Hippo pathway) in AT2 to AT1 transdifferentiation has recently been demonstrated by using small molecule inhibition and conditional knock-out in mouse lung organoids and in vivo injury experiments 17,64 , thus validating our prediction that this factor commits Krt8+ progenitors for AT1 cell fate. Moreover, an important role of beta-catenin and the canonical Wnt signaling pathways has been suggested based on in vitro differentiation of isolated AT2 cells 61 .…”

Section: Discussionsupporting

confidence: 78%

Longitudinal single cell transcriptomics reveals Krt8+ alveolar epithelial progenitors in lung regeneration

Strunz

Ansari

et al. 2019

Preprint

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Lung disease is a major health burden accounting for one in six deaths globally 1 . The lung's large surface area is exposed to a great variety of environmental and microbial insults causing injuries to its epithelium that require a regenerative response mediated by tissue-resident stem and progenitor Lung injury activates quiescent stem and progenitor cells to regenerate alveolar structures. The sequence and coordination of transcriptional programs during this process has largely remained elusive. Using single cell RNA-seq, we first generated a whole-organ bird's-eye view on cellular dynamics and cell-cell communication networks during mouse lung regeneration from ~30,000 cells at six timepoints. We discovered an injury-specific progenitor cell state characterized by Krt8 in flat epithelial cells covering alveolar surfaces. The number of these cells peaked during fibrogenesis in independent mouse models, as well as in human acute lung injury and fibrosis. Krt8+ progenitors featured a highly distinct connectome of receptor-ligand pairs with endothelial cells, fibroblasts, and macrophages. To 'sky dive' into epithelial differentiation dynamics, we sequenced >30,000 sorted epithelial cells at 18 timepoints and computationally derived cell state trajectories that were validated by lineage tracing genetic reporter mice. Airway stem cells within the club cell lineage and alveolar type-2 cells underwent transcriptional convergence onto the same Krt8+ progenitor cell state, which later resolved by terminal differentiation into alveolar type-1 cells. We derived distinct transcriptional regulators as key switch points in this process and show that induction of TNF-alpha/NFkappaB, p53, and hypoxia driven gene expression programs precede a Sox4, Ctnnb1, and Wwtr1 driven switch towards alveolar type-1 cell fate. We show that epithelial cell plasticity can induce non-gradual transdifferentiation, involving intermediate progenitor cell states that may persist and promote disease if checkpoint signals for terminal differentiation are perturbed.

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Section: Discussionsupporting

confidence: 78%

Longitudinal single cell transcriptomics reveals Krt8+ alveolar epithelial progenitors in lung regeneration

Strunz

Ansari

et al. 2019

Preprint

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“…Our trajectory model predicts distinct transcriptional regulators as candidate switch points in terminal AT1 differentiation, including TAZ (Wwtr1), Sox4 and beta-catenin (Ctnnb1). The mechanistic importance of Wwtr1 (YAP/TAZ -Hippo pathway) in AT2 to AT1 transdifferentiation has recently been demonstrated by using small molecule inhibition and conditional knockout in mouse lung organoids and in vivo injury experiments 25,55 . An important role of beta-catenin and the canonical Wnt signaling pathways has been suggested based on in vitro differentiation of isolated AT2 cells 41 .…”

Section: Discussionmentioning

confidence: 99%

Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis

et al. 2020

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The cell type specific sequences of transcriptional programs during lung regeneration have remained elusive. Using time-series single cell RNA-seq of the bleomycin lung injury model, we resolved transcriptional dynamics for 28 cell types. Trajectory modeling together with lineage tracing revealed that airway and alveolar stem cells converge on a unique Krt8 + transitional stem cell state during alveolar regeneration. These cells have squamous morphology, feature p53 and NFkB activation and display transcriptional features of cellular senescence. The Krt8+ state appears in several independent models of lung injury and persists in human lung fibrosis, creating a distinct cell-cell communication network with mesenchyme and macrophages during repair. We generated a model of gene regulatory programs leading to Krt8+ transitional cells and their terminal differentiation to alveolar type-1 cells. We propose that in lung fibrosis, perturbed molecular checkpoints on the way to terminal differentiation can cause aberrant persistence of regenerative intermediate stem cell states.

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“…Hippo signaling, which primarily mediates its signaling via Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), is an evolutionarily conserved pathway that crosses over with Wnt signaling [140,141]. TAZ is expressed by embryonic epithelium and is necessary for branching morphogenesis and alveolarization by promoting AT1 differentiation [142][143][144][145][146][147]. YAP/TAZ activity is an important transducer of extracellular cues that has important effects in fibrotic lung diseases [148].…”

Section: Dysregulated Signaling Pathways Causing Intrinsic At2 Dysfunmentioning

confidence: 99%

Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

Parimon

Yao

Stripp

et al. 2020

IJMS

262

172

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: Alveolar epithelial type II cells (AT2) are a heterogeneous population that have critical secretory and regenerative roles in the alveolus to maintain lung homeostasis. However, impairment to their normal functional capacity and development of a pro-fibrotic phenotype has been demonstrated to contribute to the development of idiopathic pulmonary fibrosis (IPF). A number of factors contribute to AT2 death and dysfunction. As a mucosal surface, AT2 cells are exposed to environmental stresses that can have lasting effects that contribute to fibrogenesis. Genetical risks have also been identified that can cause AT2 impairment and the development of lung fibrosis. Furthermore, aging is a final factor that adds to the pathogenic changes in AT2 cells. Here, we will discuss the homeostatic role of AT2 cells and the studies that have recently defined the heterogeneity of this population of cells. Furthermore, we will review the mechanisms of AT2 death and dysfunction in the context of lung fibrosis.

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TAZ is required for lung alveolar epithelial cell differentiation after injury

Cited by 67 publications

References 52 publications

Longitudinal single cell transcriptomics reveals Krt8+ alveolar epithelial progenitors in lung regeneration

Longitudinal single cell transcriptomics reveals Krt8+ alveolar epithelial progenitors in lung regeneration

Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis

Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

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