Transitional cell states sculpt tissue topology during lung regeneration

Konkimalla, Arvind; Konishi, Satoshi; Macadlo, Lauren; Kobayashi, Yoshihiko; Farino, Zachary J.; Miyashita, Naoya; El Haddad, Léa; Morowitz, Jeremy; Barkauskas, Christina E.; Agarwal, Pankaj; Souma, Tomokazu; ElMallah, Mai K.; Tata, Aleksandra; Tata, Purushothama Rao

doi:10.1016/j.stem.2023.10.001

Cited by 15 publications

(6 citation statements)

References 69 publications

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“…Intriguingly, BACH1 and EZH2 have also been associated with partial EMT in cancer 53,54 , where epithelial cells linger as heterogeneous transitional cells which do not transition into mesenchymal cells but instead exhibit a continuum of epithelial and mesenchymal traits which potentiate migration, inflammation, and tumorigenesis 55 . Lineage tracing and scRNA-seq studies indicate that AT2 transitional cells do not transform into fibroblasts via EMT 10–13 ; instead, they adopt a mixed gene expression program characterized by simultaneous expression of epithelial and mesenchymal genes, which influences lung remodeling and ECM deposition 13,56 . Recent studies showed that the accumulation of AT2 transitional cells can drive lung injury and ILD 13,56 .…”

Section: Discussionmentioning

confidence: 99%

Let-7restrains an oncogenic epigenetic circuit in AT2 cells to prevent ectopic formation of fibrogenic transitional cell intermediates and pulmonary fibrosis

Seasock,

Shafiquzzaman,

Ruiz-Echartea

et al. 2024

Preprint

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Analysis of lung alveolar type 2 (AT2) progenitor stem cells has highlighted fundamental mechanisms that direct their differentiation into alveolar type 1 cells (AT1s) in lung repair and disease. However, microRNA (miRNA) mediated post-transcriptional mechanisms which govern this nexus remain understudied. We show here that thelet-7miRNA family serves a homeostatic role in governance of AT2 quiescence, specifically by preventing the uncontrolled accumulation of AT2 transitional cells and by promoting AT1 differentiation to safeguard the lung from spontaneous alveolar destruction and fibrosis. Using mice and organoid models with genetic ablation oflet-7a1/let-7f1/let-7dcluster (let-7afd) in AT2 cells, we demonstrate prevents AT1 differentiation and results in aberrant accumulation of AT2 transitional cells in progressive pulmonary fibrosis. Integration of enhanced AGO2 UV-crosslinking and immunoprecipitation sequencing (AGO2-eCLIP) with RNA-sequencing from AT2 cells uncovered the induction of direct targets oflet-7in an oncogene feed-forward regulatory network including BACH1/EZH2 which drives an aberrant fibrotic cascade. Additional analyses by CUT&RUN-sequencing revealed loss oflet-7afdhampers AT1 differentiation by eliciting aberrant histone EZH2 methylation which prevents the exit of AT2 transitional cells into terminal AT1s. This study identifieslet-7as a key gatekeeper of post-transcriptional and epigenetic chromatin signals to prevent AT2-driven pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

Let-7restrains an oncogenic epigenetic circuit in AT2 cells to prevent ectopic formation of fibrogenic transitional cell intermediates and pulmonary fibrosis

Seasock,

Shafiquzzaman,

Ruiz-Echartea

et al. 2024

Preprint

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“…The efficient generation of transient RCS circuits is likely needed to rebuild the fibroelastic scaffold of the lung after injury. Defects in generating RCS may cause emphysema, whereas defects in resolving RCS may cause fibrosis (20,21). In nascent fibroblastic foci of early stage IPF, the myofibroblasts polarize toward basaloid cells.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously used longitudinal scRNA-seq to chart the evolution of RCS during mouse lung fibrogenesis and regeneration (18,19). Lung injury transiently induces distinct epithelial, endothelial, stromal, and immune RCS, which may form interconnected cellular circuits orchestrating fibrogenesis during regeneration and become distorted during disease (20,21). The spatiotemporal and functional interdependencies of RCS during fibrogenesis, potentially providing a conceptual framework for discovering drug targets for PF, have not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Ex vivo tissue perturbations coupled to single-cell RNA-seq reveal multilineage cell circuit dynamics in human lung fibrogenesis

Lang,

Gote-Schniering,

Porras-Gonzalez

et al. 2023

Sci. Transl. Med.

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Pulmonary fibrosis develops as a consequence of failed regeneration after injury. Analyzing mechanisms of regeneration and fibrogenesis directly in human tissue has been hampered by the lack of organotypic models and analytical techniques. In this work, we coupled ex vivo cytokine and drug perturbations of human precision-cut lung slices (hPCLS) with single-cell RNA sequencing and induced a multilineage circuit of fibrogenic cell states in hPCLS. We showed that these cell states were highly similar to the in vivo cell circuit in a multicohort lung cell atlas from patients with pulmonary fibrosis. Using micro-CT–staged patient tissues, we characterized the appearance and interaction of myofibroblasts, an ectopic endothelial cell state, and basaloid epithelial cells in the thickened alveolar septum of early-stage lung fibrosis. Induction of these states in the hPCLS model provided evidence that the basaloid cell state was derived from alveolar type 2 cells, whereas the ectopic endothelial cell state emerged from capillary cell plasticity. Cell-cell communication routes in patients were largely conserved in hPCLS, and antifibrotic drug treatments showed highly cell type–specific effects. Our work provides an experimental framework for perturbational single-cell genomics directly in human lung tissue that enables analysis of tissue homeostasis, regeneration, and pathology. We further demonstrate that hPCLS offer an avenue for scalable, high-resolution drug testing to accelerate antifibrotic drug development and translation.

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“…Given the widespread and nonselective injury induced by bleomycin and LPS, the contribution of other cell types and potential AT1 cell dysfunction in driving aberrant AT2 cell transdifferentiation and the emergence of the Krt8 + reprogrammed transitional cell state has been debated (35). In subsequent studies, this cell state has been identified in genetic models with selective AT2 cell modification, including models of accelerated senescence of AT2 cells via Trp53 activation, surfactant metabolism dysfunction (Sftpc C185G mice), and Nkx2.1 ablation in alveolar epithelial progenitors (24,36,37).…”

Section: Discussionmentioning

confidence: 99%

Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome pulmonary fibrosis

Wang

Michki

Banaschewski

et al. 2023

Preprint

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Hermansky-Pudlak syndrome (HPS) is a genetic disorder of intracellular endosomal trafficking defects associated with pulmonary fibrosis. Double mutant HPS1/2 mice exhibit spontaneous fibrosis and single mutant HPS1 and HPS2 mice display increased fibrotic sensitivity. To identify mechanisms of AT2 cell dysfunction contributing to fibrosis in HPS, we examined lungs from aged HPS1/2 mice and observed regions of AT2 cell loss adjacent to areas of marked AT2 cell hyperplasia as compared to wild type (WT). Overall, there was accelerated loss of AT2 cells in HPS1/2, HPS1, and HPS2 mice with aging based on immunohistochemistry and lineage tracing studies. Lung organoids generated with HPS2 AT2 cells with WT fibroblasts were smaller in size and displayed significantly decreased colony forming efficiency compared to organoids with WT AT2 cells. Utilizing an H1N1 PR8 influenza model to examine AT2 cell regeneration after injury, there was a significant decrease in the percentage of proliferating AT2 cells in HPS1 and HPS2 mice compared to WT mice. RNA sequencing of AT2 cells isolated from unchallenged mice demonstrated upregulation of genes associated with proliferation and cellular senescence in HPS AT2 cells. Collectively, AT2 cells in HPS mice exhibit dysregulated proliferation with transcriptomic features suggesting subpopulations of senescent and hyperproliferative cells. Dysregulated maintenance of the alveolar epithelium with accelerated senescence and aberrant proliferation of AT2 cells appears to be a shared pathway underlying HPS and other sporadic and genetic forms of pulmonary fibrosis.

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Transitional cell states sculpt tissue topology during lung regeneration

Cited by 15 publications

References 69 publications

Let-7restrains an oncogenic epigenetic circuit in AT2 cells to prevent ectopic formation of fibrogenic transitional cell intermediates and pulmonary fibrosis

Let-7restrains an oncogenic epigenetic circuit in AT2 cells to prevent ectopic formation of fibrogenic transitional cell intermediates and pulmonary fibrosis

Ex vivo tissue perturbations coupled to single-cell RNA-seq reveal multilineage cell circuit dynamics in human lung fibrogenesis

Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome pulmonary fibrosis

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