Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA340019 | ENA |
REPOSITORIES: ENA
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Project description:A hallmark of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases is dysregulated repair of the alveolar epithelium. The Hippo pathway effector transcription factors YAP and TAZ are implicated as essential for type 1 and type 2 alveolar epithelial cell (AT1 and AT2) differentiation in the developing lung, yet aberrant activation of YAP/TAZ is a prominent feature of the dysregulated alveolar epithelium in IPF. In these studies, we sought to define the functional role of YAP/TAZ activity during alveolar regeneration. We demonstrated that Yap and Taz are normally activated in AT2 cells shortly after injury, and deletion of Yap/Taz in AT2 cells led to pathologic alveolar remodeling, failure of AT2 to AT1 cell differentiation, increased collagen deposition, exaggerated neutrophilic inflammation, and increased mortality following injury induced by a single dose of bleomycin. Loss of Yap/Taz activity prior to a LPS injury prevented AT1 cell regeneration, led to intra-alveolar collagen deposition, and resulted in persistent innate inflammation. Together these findings established that AT2 cell Yap/Taz activity is essential for functional alveolar epithelial repair and prevention of fibrotic remodeling.
2023-11-15 | GSE243135 | GEO
Project description:YAP/TAZ signaling is required for initiation of lung alveolar repair, yet previous studies in idiopathic pulmonary fibrosis (IPF) predicted increased YAP/TAZ signaling in alveolar epithelial cells (AECs). We investigated whether persistent YAP/TAZ AEC signaling contributes to failed epithelial repair and persistent fibrotic remodeling. In IPF lungs, we identified increased YAP+/TAZ+ AECs and increased transcriptional target expression. Pharmacological YAP/TAZ activation in human AEC organoids and in murine AT2 cell organoids generated with genetic Yap/Taz activation (YTactive) (via deletion of Hippo-kinases Stk3/4), resulted in phenotype shifts into aberrant transitional and airway-like states. Bleomycin injury of YTactive mice resulted in persistent fibrotic remodeling at 28- and 56-days post-bleomycin injury. Gene promoter activity associated with transitional cell markers (Krt19, Hopx, and Runx2) was increased in YTactive AT2 cells. Immunofluorescent staining showed a loss of AT2 associated Cebpa and increased Krt19 in YTactive lineage traced AT2 cells 28 days post-injury. Inhibition of Yap/Taz using Verteporfin resulted in improved lung repair in YTactive mouse lungs, including restored Cebpa and decreased Krt19+ transitional cells. These findings demonstrate sustained Yap/Taz activation drives abnormal alveolar repair and persistent fibrotic remodeling. Blocking aberrant persistent Yap/Taz activity promotes adaptive repair and has potential as a therapeutic strategy for pulmonary fibrosis.
2026-06-02 | GSE327686 | GEO
Project description:YAP/TAZ signaling is required for initiation of lung alveolar repair, yet previous studies in idiopathic pulmonary fibrosis (IPF) predicted increased YAP/TAZ signaling in alveolar epithelial cells (AECs). We investigated whether persistent YAP/TAZ AEC signaling contributes to failed epithelial repair and persistent fibrotic remodeling. In IPF lungs, we identified increased YAP+/TAZ+ AECs and increased transcriptional target expression. Pharmacological YAP/TAZ activation in human AEC organoids and in murine AT2 cell organoids generated with genetic Yap/Taz activation (YTactive) (via deletion of Hippo-kinases Stk3/4), resulted in phenotype shifts into aberrant transitional and airway-like states. Bleomycin injury of YTactive mice resulted in persistent fibrotic remodeling at 28- and 56-days post-bleomycin injury. Gene promoter activity associated with transitional cell markers (Krt19, Hopx, and Runx2) was increased in YTactive AT2 cells. Immunofluorescent staining showed a loss of AT2 associated Cebpa and increased Krt19 in YTactive lineage traced AT2 cells 28 days post-injury. Inhibition of Yap/Taz using Verteporfin resulted in improved lung repair in YTactive mouse lungs, including restored Cebpa and decreased Krt19+ transitional cells. These findings demonstrate sustained Yap/Taz activation drives abnormal alveolar repair and persistent fibrotic remodeling. Blocking aberrant persistent Yap/Taz activity promotes adaptive repair and has potential as a therapeutic strategy for pulmonary fibrosis.
2026-06-02 | GSE327565 | GEO
Project description:Proper lung function relies on precisely balanced numbers of specialized epithelial cell types that work together and are maintained in homeostasis. We describe essential roles for the transcriptional regulators Yap and Taz, which are key effectors of Hippo pathway signaling, in maintaining lung epithelial homeostasis. We report that conditional deletion of Yap1/Yap and Wwtr1/Taz in the lung epithelium of adult mice results in severe defects with consequent animal lethality. Phenotypes associated with Yap/Taz deletion include alveolar defects and a striking development of goblet cell metaplasia throughout the airways. We performed gene expression analysis of wild type and Yap/Taz null primary mouse airway epithelial cells in order to define Yap/Taz controlled gene expression.
2021-08-09 | GSE156525 | GEO
Project description:Proper lung function relies on precisely balanced numbers of specialized epithelial cell types that work together and are maintained in homeostasis. In this study we have described essential roles for the transcriptional regulators YAP and TAZ, which are key effectors of Hippo pathway signaling, in maintaining lung epithelial homeostasis. Phenotypes associated with Yap/Taz deletion include alveolar defects and a striking development of goblet cell metaplasia throughout the airways. Lineage specific deletion of Yap and Taz in Scgb1a1+ cells leads to increased Mucin production within the knockout cells in vivo. In order better characterize the in vivo transcriptional changes associated with Yap/Taz knockout in these cells, we have isolated Scgb1a1 lineage traced cells from control and yap/taz cNull mice and performed bulk RNA sequencing.
2021-08-09 | GSE171712 | GEO
Project description:Proper lung function relies on precisely balanced numbers of specialized epithelial cell types that work together and are maintained in homeostasis. In this study we have described essential roles for the transcriptional regulators YAP and TAZ, which are key effectors of Hippo pathway signaling, in maintaining lung epithelial homeostasis. Phenotypes associated with Yap/Taz deletion include alveolar defects and a striking development of goblet cell metaplasia throughout the airways. Knockdown of YAP and TAZ in HBECs similarly drives mucin expression. The TEAD family of transcription factors are well characterized partners of the YAP/TAZ transcriptional effectors, and we have found that knockdown of TEAD1-4 similarly drives elevated mucin expression. In order to further understand the role of the TEAD transcription factors in human lung epithelial cell fate, we conducted TEAD Chromatin Immunopreciptitation (ChIP)-Sequencing.
2021-08-19 | GSE158306 | GEO
Project description:Proper lung function relies on precisely balanced numbers of specialized epithelial cell types that work together and are maintained in homeostasis. In this study we have described essential roles for the transcriptional regulators YAP and TAZ, which are key effectors of Hippo pathway signaling, in maintaining lung epithelial homeostasis. Phenotypes associated with Yap/Taz deletion include alveolar defects and a striking development of goblet cell metaplasia throughout the airways. Knockdown of YAP and TAZ in HBECs similarly drives mucin expression. The TEAD family of transcription factors are well characterized partners of the YAP/TAZ transcriptional effectors, and we have found that knockdown of TEAD1-4 similarly drives elevated mucin expression. In order to further understand the role of the TEAD transcription factors in human lung epithelial cell fate, we conducted TEAD Chromatin Immunopreciptitation (ChIP)-Sequencing.
2021-08-19 | GSE158305 | GEO
Project description:The Hippo signaling pathway, mediated by its transcriptional effectors YAP and TAZ, play vital roles in maintaining lung homeostasis and facilitating injury repair. While the roles of the Hippo pathway in epithelial cells are well-established, its regulatory effects on lung fibroblasts remain less understood. Here, we engineered a novel mouse allele to allow inducible knockdown of YAP and TAZ, and show that fibroblast-specific knockdown enhances the ability of PDGFRa+ alveolar fibroblasts to support organoids derived from alveolar epithelial stem cells in vitro. Single-cell multiomic profiling revealed changes in fibroblast subpopulations, including the emergence of an Mmp9+ cluster containing Wnt4+ cells. Analyses demonstrated shifts in the epigenomic landscape leading to varied enrichment of transcription factor motifs across both fibroblasts and epithelial cells in response to targeted suppression of YAP/TAZ in fibroblasts. Further computational analyses identified an increase in epithelial Wnt signaling which was confirmed by in vivo studies. We found that Wnt4 expression was increased in PDGFRa-lineage+ fibroblasts and enhanced proliferation of SPC+ AT2 cells following fibroblast-specific YAP/TAZ knockdown. These results shed new light on the mechanistic role of YAP/TAZ in PDGFRa+ alveolar fibroblasts in supporting AT2 cell maintenance and proliferation via Wnt4 secretion.
2025-04-10 | GSE291641 | GEO
Project description:The Hippo signaling pathway, mediated by its transcriptional effectors YAP and TAZ, play vital roles in maintaining lung homeostasis and facilitating injury repair. While the roles of the Hippo pathway in epithelial cells are well-established, its regulatory effects on lung fibroblasts remain less understood. Here, we engineered a novel mouse allele to allow inducible knockdown of YAP and TAZ, and show that fibroblast-specific knockdown enhances the ability of PDGFRa+ alveolar fibroblasts to support organoids derived from alveolar epithelial stem cells in vitro. Single-cell multiomic profiling revealed changes in fibroblast subpopulations, including the emergence of an Mmp9+ cluster containing Wnt4+ cells. Analyses demonstrated shifts in the epigenomic landscape leading to varied enrichment of transcription factor motifs across both fibroblasts and epithelial cells in response to targeted suppression of YAP/TAZ in fibroblasts. Further computational analyses identified an increase in epithelial Wnt signaling which was confirmed by in vivo studies. We found that Wnt4 expression was increased in PDGFRa-lineage+ fibroblasts and enhanced proliferation of SPC+ AT2 cells following fibroblast-specific YAP/TAZ knockdown. These results shed new light on the mechanistic role of YAP/TAZ in PDGFRa+ alveolar fibroblasts in supporting AT2 cell maintenance and proliferation via Wnt4 secretion.
2025-04-10 | GSE291640 | GEO
Project description:To define the role of Yap/Taz in alveolar epithelial regeneration, we deleted Yap/Taz in mouse lung Spc-expressing ATII cells by using Spc-CreERT2, Yap fl/fl, Taz fl/fl, R26R-mTmG mice. This data set contains the microarrays examining gene expression in the lineage-labeled Spc-expressing ATII cells before and after Streptococcus pneumoniae infection.
2018-12-01 | GSE86027 | GEO