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Genome-wide expression analysis of EPCAM+ epithelial cells from 3-dimensional lung organoids harboring Hermansky-Pudlak Syndrome-associated mutations

ABSTRACT: Genome-wide expression analysis of EPCAM+ epithelial cells from 3-dimensional lung organoids harboring Hermansky-Pudlak Syndrome-associated mutations

PROVIDER: PRJNA502562 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8137610.fastq.gz	Fastqsanger.gz
	SRR8137611.fastq.gz	Fastqsanger.gz
	SRR8137602.fastq.gz	Fastqsanger.gz
	SRR8137612.fastq.gz	Fastqsanger.gz
	SRR8137603.fastq.gz	Fastqsanger.gz

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Genome-wide expression analysis of EPCAM+ epithelial cells from 3-dimensional lung organoids harboring Hermansky-Pudlak Syndrome-associated mutations

Project description:Introduction of Hermansky-Pudlak Syndrome-associated mutations with CRISPR/Cas9 genome editing, allows for disease modeling in 3D cultures of hPSC-derived lung organoids.

2019-06-25 | GSE121999 | GEO

Dysregulated alveolar epithelial maintenance in Hermansky-Pudlak syndrome pulmonary fibrosis

Project description:Dysregulated alveolar epithelial maintenance in Hermansky-Pudlak syndrome pulmonary fibrosis

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Emergence of inflammatory fibroblasts with aging in Hermansky-Pudlak syndrome associated pulmonary fibrosis

Project description:The longitudinal cellular interactions that drive pulmonary fibrosis are not well understood. To investigate the disease underpinnings associated with fibrosis onset and progression, we generated a scRNAseq atlas of lungs from young and aged mouse models of multiple subtypes of Hermansky-Pudlak syndrome (HPS), a collection of rare autosomal recessive diseases associated with albinism, platelet dysfunction, and pulmonary fibrosis. We identified an age-dependent increase in SAA3+ inflammatory lung fibroblasts in HPS mice, including in double-mutant HPS1-2 mice which develop spontaneous fibrosis. HPS1 fibroblasts showed increased expression of IL-1R1, whereas alveolar type II epithelial cells from HPS2 mice induced the inflammatory gene signature in co-cultured fibroblasts. scRNAseq of lung tissue from three HPS1 patients similarly showed the presence of inflammatory fibroblasts and increased IL1R1 expression on fibroblasts. These data posit complex interactions between dysfunctional epithelial cells, inflammatory fibroblasts, and recruited immune cells, suggesting potential opportunities for mitigation of the fibrotic cascade.

2025-02-07 | GSE272904 | GEO

Type 2 innate immunity promotes the development of pulmonary fibrosis in Hermansky-Pudlak syndrome

Project description:Hermansky-Pudlak syndrome (HPS), particularly in types 1 and 4, is characterized by progressive pulmonary fibrosis, a major cause of morbidity and mortality. However, the precise mechanisms driving pulmonary fibrosis in HPS are not fully elucidated. Our previous studies have suggested that CHI3L1-driven fibroproliferation may be a significant factor in HPS-associated fibrosis. This study aimed to explore the role of CHI3L1-CRTH2 interaction on ILC2s and explored the potential contribution of ILC2-fibroblast crosstalk in the development of pulmonary fibrosis in HPS. We identified ILC2s in lung tissues from idiopathic pulmonary fibrosis (IPF) and HPS patients. Our findings suggest that ILC2s may directly stimulate the proliferation and differentiation of primary lung fibroblasts partially through Areg-EGFR-dependent mechanisms. Additionally, specific overexpression of CHI3L1 in the ILC2 population using the IL-7Rcre driver, which was associated with increased fibroproliferation, indicates that ILC2-mediated, CRTH2-dependent mechanisms might contribute to optimal CHI3L1-induced fibroproliferative repair in HPS-associated pulmonary fibrosis.

2024-10-11 | GSE278788 | GEO

Dysregulated alveolar epithelial maintenance in Hermansky-Pudlak syndrome pulmonary fibrosis

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

Emergence of inflammatory fibroblasts with aging in Hermansky-Pudlak syndrome associated pulmonary fibrosis

Project description:Emergence of inflammatory fibroblasts with aging in Hermansky-Pudlak syndrome associated pulmonary fibrosis

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Type 2 innate immunity promotes the development of pulmonary fibrosis in Hermansky-Pudlak syndrome

Project description:Type 2 innate immunity promotes the development of pulmonary fibrosis in Hermansky-Pudlak syndrome

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Modeling of lung phenotype of Hermansky-Pudlak syndrome type I using patient-specific iPS cells

Project description:Modeling of lung phenotype of Hermansky-Pudlak syndrome type I using patient-specific iPS cells

| PRJNA745557 | ENA

Insights into the renal pathophysiology in Hermansky-Pudlak syndrome-1 from urinary extracellular vesicle proteomics and a new mouse model

Project description:Hermansky-Pudlak syndrome type 1 (HPS-1) is a rare, autosomal recessive disorder caused by defects in the biogenesis of lysosome-related organelles complex-3 (BLOC-3). Impaired kidney function is among its clinical manifestations. To investigate HPS-1 renal involvement, we employed 1D-gel-LC–MS/MS and compared the protein composition of urinary extracellular vesicles (uEVs) from HPS-1 patients to normal control individuals. We identified 1029 proteins, 149 of which were altered in HPS-1 uEVs. Ingenuity Pathway Analysis revealed disruptions in mitochondrial function and the LXR/RXR pathway that regulates lipid metabolism, which is supported by our novel Hps1 knockout mouse. Serum concentration of the LXR/RXR pathway protein ApoA1 in our patient cohort was positively correlated with kidney function (with the estimated glomerular filtration rate or eGFR). uEVs can be used to study epithelial cell protein trafficking in HPS-1 and may provide outcome measures for HPS-1 therapeutic interventions.

2025-07-07 | PXD063765 | Pride

Hermansky-Pudlak syndrome type 1 causes impaired anti-microbial immunity through a pathogenic lipid metabolism-mTOR circuit

Project description:Mendelian diseases that present with immune-mediated disorders can provide insights into the molecular mechanisms that drive inflammation. Hermansky-Pudlak syndrome (HPS) types 1 and 4 are caused by defective vesicle trafficking involving the BLOC-3 complex. The presence of inflammatory complications such as Crohn’s disease-like inflammation and lung fibrosis in these patients remains enigmatic. Using mass cytometry we observe an augmented inflammatory monocyte compartment in HPS1 patient peripheral blood that may be associated with a TNF - and IL-1α-dominated cytokine dysregulation. HPS1 patient monocyte-derived macrophages express an inflammatory TNF-OSM mRNA gene signature and changes in lipid metabolism. Using stimulation experiments and lysosomal proteomics we show that defective lipid metabolism drives RAB32-dependent mTOR signaling, facilitated by the accumulation of mTOR on lysosomes. This pathogenic circuit translates into aberrant bacterial clearance, which can be rescued with mTORC1 inhibition. We reveal that a pathogenic lipid-mTOR signaling circuit acts as a metabolic checkpoint for defective anti-microbial activity. This mechanism may be relevant to the complex pathology of HPS1 patients featuring macrophage lipid accumulation, granuloma formation, defective anti-microbial activity and tissue inflammation. Lastly, this circuit may be present in a wider group of disorders with defective lipid metabolism and cholesterol accumulation.

2022-11-02 | PXD024435 | Pride

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