Spatial transcriptomic comparison between IPF and donor lung distal explant tissue
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE292956 | GEO | 2026/03/01
REPOSITORIES: GEO
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Project description:Pulmonary fibrosis remains a significant public health concern due to an increasing incidence and limited treatment options. Alveolar type 2 epithelial cell (AT2) senescence causes stem cell exhaustion and progenitor failure, leading to ineffective and aberrant alveolar repairs and unresolved fibrosis. AT2 senescence regulatory molecules require additional studies. We demonstrate that the overexpression of syndecan-1 on IPF-AT2 cells is positively associated with the AT2 composite transcriptomic senescence score (SenMayo Senescence Score) and cellular senescence proteins. These findings imitate those of young and aged bleomycin-injured wild-type (WT) mice. The roles of syndecan-1 in regulating AT2 cellular senescence are corroborated in human and mouse lung epithelial cell lines. Functionally, the AT2 alveolospheres from bleomycin-injured Sdc1–/– mice had higher colony-forming efficiency (CFE) and normal differentiation, whereas WT alveolospheres were less proliferative and aberrant differentiation. Using precision-cut lung slices (PCLS), bleomycin-injured WT lungs had lower AT2 cells and a lower secretory surfactant protein C than Sdc1–/– PCLS, indicating the detrimental role of excess syndecan-1. We further showed that the transcriptomic p53 activity score is higher in IPF and bleomycin-injured WT AT2 cells compared to Sdc1–/– AT2 cells. Additionally, syndecan-1 activated p53 by inducing acetylation at lysine379. Our work indicates that syndecan-1 reprograms AT2 cells to become senescent during lung fibrogenesis and likely through the p53 signaling pathway.
2026-03-01 | GSE292961 | GEO
Project description:Spatial transcriptomic comparison between IPF and donor lung distal explant tissue
| PRJNA1242230 | ENA
Project description:Alveoli are thin-walled sacs that serve as the gas exchange units of the lung. They are affected in devastating lung diseases including COPD, Idiopathic Pulmonary Fibrosis, and the major form (adenocarcinoma) of lung cancer, the leading cause of cancer deaths. The alveolar epithelium is composed of two morphologically distinct cell types: alveolar type (AT) 1 cells, exquisitely thin cells across which oxygen diffuses to reach the blood, and AT2 cells, specialized surfactant-secreting cells. Classical studies suggested that AT1 cells arise from AT2 cells during development and following injury, but more recent studies suggest other sources. Here we use histological and marker analysis, lineage tracing, and clonal analysis in mice to identify alveolar progenitor and stem cells and map their locations and potential in vivo. The results show that AT1 and AT2 cells arise independently during development from a bipotential progenitor. After birth, new AT1 cells derive from rare, long-lived, self-renewing AT2 cells, each producing a slowly expanding clonal focus of regenerated alveoli contiguous with the founder AT2 cell. This stem cell function of AT2 cells is broadly activated by diffuse AT1 cell injury, and AT2 self-renewal can be induced in vitro by EGF ligands and permanently activated in vivo by AT2 cell-specific targeting of the oncogenic KrasG12D allele, efficiently transforming AT2 cells into monoclonal adenomatous tumors that rapidly enlarge and prove fatal. Thus, there is a developmental switch in alveolar progenitor cells after birth, when mature AT2 cells function as facultative stem cells that contribute to local alveolar renewal, repair, and cancer. We propose that short-range signals from dying AT1 cells regulate AT2 stem cell activity: a signal transduced by EGFR-KRAS controls AT2 self-renewal and is hijacked during oncogenic transformation, and a separate signal controls reprogramming to AT1 cell fate. To compare expression between ATII and E18 BP populations, RNA was isolated from either population purified by FACS. Two populations are analyzed with 3 biological replicates per population.
2014-03-07 | E-GEOD-49346 | biostudies-arrayexpress
Project description:Idiopathic pulmonary fibrosis (IPF) is a disease related to AT2 cell. We used flow cytometry to analyze the epithelial component of donor and IPF lungs. From the live cells, we first excluded the CD31PosCD45Pos and then selected the EPCAMPos cells for further analysis using the human AT2 cell marker HTll-280 and the surface marker PD-L1. Our data indicate that, the bona fide differentiated AT2 cells (HTll-280High PD-L1Neg), were drastically reduced in the context of IPF. More interestingly, the number of HTll-280Low/Neg PD-L1High was drastically increased, suggesting that HTll-280Low PD-L1High epithelial cells could represent a pool of progenitors linked to the deficient AT2 lineage. The aim of this experiment is further characterization of AT2 and PDL1+ cells in donor and IPF.
2023-01-01 | GSE195770 | GEO
Project description: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.
2025-01-08 | GSE235628 | GEO
Project description:Alveolar type 2 (AT2) organoids, derived from induced pluripotent stem cells, were stimulated with a fibrosis cocktail containing the pro-fibrotic and inflammatory cytokines TGF-β (5 ng/ml), TNF-α (10 ng/ml), PDGF-AB (10 ng/ml) and LPA (5 μM) or control cocktail containing diluents for 72 h.
2023-05-22 | E-MTAB-11676 | biostudies-arrayexpress
Project description:Idiopathic pulmonary fibrosis (IPF) is a fatal form of interstitial lung disease associated with progressive scarring of lung tissue and declining pulmonary function in aging individuals. Here we employ data mining and single cell RNA sequencing (scRNAseq) to define candidate drivers of AT2 senescence in IPF lung tissue. We show that AT2 cells isolated from IPF lung tissue exhibit characteristic features of cellular senescence and reduced abundance of Sin3a, critical determinant of endodermal progenitor cell maintenance in the developing lung. Conditional loss of Sin3a within AT2 cells of the adult mouse lung activated a program of p53-dependent cellular senescence and AT2 cell depletion, leading to progressive pulmonary fibrosis. In contrast, ablation of AT2 cells through conditional activation of a DTA toxin gene led to transient fibrosis that resolved over time, suggesting that senescence of AT2 cells was a critical driver of progressive fibrosis. Activation of b6 integrin was observed within a subset of AT2 cells with Sin3a loss-of-function that localized to the advancing margin of advancing fibroproliferative lesions. Systemic inhibition of TGF signaling or delivery of senolytic drugs prevented lung fibrosis in Sin3a loss-of-function mice. Our findings establish a novel mouse model that recapitulates key pathological features of human IPA and show that p53-dependent senescence is a proximal regulator of TGF induction and progressive pulmonary fibrosis.
2020-06-30 | GSE132910 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a fatal form of interstitial lung disease associated with progressive scarring of lung tissue and declining pulmonary function in aging individuals. Here we employ data mining and single cell RNA sequencing (scRNAseq) to define candidate drivers of AT2 senescence in IPF lung tissue. We show that AT2 cells isolated from IPF lung tissue exhibit characteristic features of cellular senescence and reduced abundance of Sin3a, critical determinant of endodermal progenitor cell maintenance in the developing lung. Conditional loss of Sin3a within AT2 cells of the adult mouse lung activated a program of p53-dependent cellular senescence and AT2 cell depletion, leading to progressive pulmonary fibrosis. In contrast, ablation of AT2 cells through conditional activation of a DTA toxin gene led to transient fibrosis that resolved over time, suggesting that senescence of AT2 cells was a critical driver of progressive fibrosis. Activation of b6 integrin was observed within a subset of AT2 cells with Sin3a loss-of-function that localized to the advancing margin of advancing fibroproliferative lesions. Systemic inhibition of TGF signaling or delivery of senolytic drugs prevented lung fibrosis in Sin3a loss-of-function mice. Our findings establish a novel mouse model that recapitulates key pathological features of human IPA and show that p53-dependent senescence is a proximal regulator of TGF induction and progressive pulmonary fibrosis.
2020-06-30 | GSE132914 | GEO
Project description:Telomere dysfunction in type II alveolar epithelial (AT2) cells causes pulmonary fibrosis in a subset of patients. TRF2 is a key component of the shelterin complex (SC) which prevents abnormally shortened and uncapped telomeres and genetic variants of SC were reported in some familial cases of IPF. We conceived that in vitro senescence model of AT2 cells derived from human induced pluripotent stem cells (iPSCs) would be beneficial for elucidating the mechanism of IPF progression. Then we generated an iPSC line using a doxycycline (dox) -inducible lentiviral vector encoding the dominant negative variant of TRF2 (TRF2DN). We next differentiated this iPSC line into AT2 (iAT2) cells and expressed TRF2DN protein in a dox-inducible manner. Alveolar organoids consisting of TRF2DN-expressing iAT2 cells and human fetal lung fibroblasts showed contraction of the organoid matrices
2026-02-18 | GSE289682 | GEO
Project description:Telomere dysfunction in type II alveolar epithelial (AT2) cells causes pulmonary fibrosis in a subset of patients. TRF2 is a key component of the shelterin complex (SC) which prevents abnormally shortened and uncapped telomeres and genetic variants of SC were reported in some familial cases of IPF. We conceived that in vitro senescence model of AT2 cells derived from human induced pluripotent stem cells (iPSCs) would be beneficial for elucidating the mechanism of IPF progression. Then we generated an iPSC line using a doxycycline (dox) -inducible lentiviral vector encoding the dominant negative variant of TRF2 (TRF2DN). We next differentiated this iPSC line into AT2 (iAT2) cells and expressed TRF2DN protein in a dox-inducible manner. Alveolar organoids consisting of TRF2DN-expressing iAT2 cells and human fetal lung fibroblasts showed contraction of the organoid matrices
2026-02-18 | GSE289679 | GEO