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Triggering AHR resolves TGF-β1 induced fibroblast activation and promotes AT1 cell regeneration in alveolar organoids

ABSTRACT: Triggering AHR resolves TGF-β1 induced fibroblast activation and promotes AT1 cell regeneration in alveolar organoids

PROVIDER: PRJNA1122846 | ENA |

REPOSITORIES: ENA

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Triggering AHR resolves TGF-β1 induced fibroblast activation and promotes AT1 cell regeneration in alveolar organoids

Project description:Regeneration of the alveolar epithelium is necessary to restore tissue architecture and gas exchange capabilities in chronic pulmonary diseases such as fibrosing interstitial lung disease. While it is known alveolar type 2 (AT2) cells give rise to alveolar type 1 (AT1) cells to repair the alveolar epithelium after injury, methods to promote this process under pathological settings are poorly understood. Here, using a complex 3D organoid culture with TGF-β1 dependent impaired AT1 spheroid formation, we performed a high-throughput screen (HTS) with ∼16,800 compounds to identify small molecules that increase number of AT1 spheroids. Longitudinal single cell RNA sequencing (scRNA-seq) revealed that DB-11-BE87 increased AT1 regeneration by reducing TGF-β1 induced fibroblast activation, concurrently with AHR activation in those cells. These studies highlight a novel HTS system to identify factors that can promote AT1 differentiation and suggest AHR activation as a method to counteract pathological TGF-β1 signaling in pulmonary disease.

2025-06-23 | GSE269634 | GEO

Gold Compound Induces Immune Suppression via AHR-TGF-β1 Signaling

Project description:Gold Compound Induces Immune Suppression via AHR-TGF-β1 Signaling

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Tgfb in AT1 cells

Project description:Premature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease increasing in incidence which disrupts lung health throughout the lifespan. The TGFβ superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show that the primary TGFβ receptor, Tgfbr2, is critical for AT1 cell fate maintenance and function. Loss of Tgfbr2 in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming. Transcriptomic and proteomic analysis reveal that expression of extracellular matrix components by AT1 cells is attenuated with loss of Tgfbr2. Cell spreading assays shows that TGFβ signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGFβ signaling to maintain AT1 fate and define this cell lineage as a major orchestrator of the alveolar matrisome, which, if altered, may predispose to BPD.

2024-03-04 | GSE230268 | GEO

Tgfb in AT1 cells

Project description:Tgfb in AT1 cells

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Gold Compound Induces Immune Suppression via AHR-TGF-β1 Signaling

Project description:Gold compounds containing planar N-heterocyclic (NHC) carbene ligands are potent aryl hydrocarbon receptor (AHR) ligands. Further studies with the lead compound (called MC3), show that MC3 activates TGFβ signaling while repressing CD4+ T-cell activation in vitro, in human and mouse T-cells, and in scurfy mouse, while repression of AHR activity or TGFβ-SMAD cascades compensated its immune suppressive function. The in-vivo induction of Tgfb1 expression was associated with reduced severity of the autoimmune markers.

2019-01-16 | GSE125146 | GEO

Bradyrhizobium sp. AT1

Project description:Bradyrhizobium sp. AT1 Genome sequencing and assembly

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N-Acetylation of secreted proteins is widespread in Apicomplexa and independent of acetyl-CoA transporter AT1

Project description:Acetyl-CoA critically participates in post-translational modification of proteins, central carbon and lipid metabolism in several compartments of eukaryotic cells. In mammals, the acetyl-CoA transporter 1 (AT1) facilitates the flux of cytosolic acetyl-CoA into the endoplasmic reticulum (ER) enabling the acetylation of proteins of the secretory pathway in concert with dedicated acetyltransferases including Nat8. Homologues of AT1 and Nat8 were identified in the apicomplexan parasites Toxoplasma gondii and Plasmodium berghei. However, the implication of acetyl-CoA pool influx into the ER in acetylation of ER-transiting proteins and their relevance throughout the parasites’ life cycle is unknown. Here, we report proteome-wide analyses, which revealed unprecedented widespread N-terminal acetylation marks of secreted proteins in both parasites. Deletion of the gene coding for AT1 in both parasites, resulted in global loss of fitness and in addition to retardation in erythrocytic development, malaria parasites are blocked in transmission to mosquitoes. However, in absence of AT1 proteome wide lysine and N-terminal acetylation modifications remain unaltered. This highlights a role of AT1 in parasite development uncoupled to acetylation capacity, indicative of an unusually active acetylation machinery occurring in the ER of Apicomplexa.

2022-06-20 | PXD029616 | Pride

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Project description:These data show that the genes that distinguish myofibroblasts from fibroblasts are myriad, and that some genes not traditionally associated with myofibroblast differentiation may serve as novel therapeutic targets for fibrosing disorders. Gene expression levels were assessed from total RNA on the Affymetrix U219 microarray. Here, we use transforming growth factor-β1 (TGF-β1) and prostaglandin E2 (PGE2), which has recently been shown to reverse myofibroblast differentiation, to investigate the transcriptomic changes that occur during TGF-β1-induced differentiation and PGE2-induced de-differentiation of myofibroblasts.

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