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

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

PROVIDER: PRJNA745557 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15100865_1.fastq.gz	Fastqsanger.gz
	SRR15100865_2.fastq.gz	Fastqsanger.gz
	SRR15100866_1.fastq.gz	Fastqsanger.gz
	SRR15100866_2.fastq.gz	Fastqsanger.gz
	SRR15100867_1.fastq.gz	Fastqsanger.gz

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Modeling of lung phenotype of Hermansky-Pudlak syndrome type I using patient-specific iPS cells (NaPi2Bhigh cells)

Project description:Modeling of lung phenotype of Hermansky-Pudlak syndrome type I using patient-specific iPS cells (NaPi2Bhigh cells)

| PRJNA745560 | ENA

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

Modeling of lung phenotype of Hermansky-Pudlak syndrome type I using patient-specific iPS cells (SPC positive cells)

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

| PRJNA745559 | ENA

Modeling of lung phenotype of Hermansky-Pudlak syndrome type I using patient-specific iPS cells (NaPi2Bhigh cells)

Project description:We generated iPSCs from HPS1 patient-derived fibroblasts with bi-allelic c.1472_1487dup16 variant in HPS1 gene and their gene-corrected ones and differentiated them into alveolar epithelial cells in organoids for disease modeling of HPS1.

2021-11-04 | GSE179899 | GEO

Modeling of lung phenotype of Hermansky-Pudlak syndrome type I using patient-specific iPS cells (SPC positive cells)

2021-11-04 | GSE179898 | GEO

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-11-04 | GSE179900 | 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

Modeling of lung phenotype of Hermansky-Pudlak syndrome type I using patient-specific iPSCs.

Project description:BackgroundSomatic cells differentiated from patient-specific human induced pluripotent stem cells (iPSCs) could be a useful tool in human cell-based disease research. Hermansky-Pudlak syndrome (HPS) is an autosomal recessive genetic disorder characterized by oculocutaneous albinism and a platelet dysfunction. HPS patients often suffer from lethal HPS associated interstitial pneumonia (HPSIP). Lung transplantation has been the only treatment for HPSIP. Lysosome-related organelles are impaired in HPS, thereby disrupting alveolar type 2 (AT2) cells with lamellar bodies. HPSIP lungs are characterized by enlarged lamellar bodies. Despite species differences between human and mouse in HPSIP, most studies have been conducted in mice since culturing human AT2 cells is difficult.MethodsWe generated patient-specific iPSCs from patient-derived fibroblasts with the most common bi-allelic variant, c.1472_1487dup16, in HPS1 for modeling severe phenotypes of HPSIP. We then corrected the variant of patient-specific iPSCs using CRISPR-based microhomology-mediated end joining to obtain isogenic controls. The iPSCs were then differentiated into lung epithelial cells using two different lung organoid models, lung bud organoids (LBOs) and alveolar organoids (AOs), and explored the phenotypes contributing to the pathogenesis of HPSIP using transcriptomic and proteomic analyses.ResultsThe LBOs derived from patient-specific iPSCs successfully recapitulated the abnormalities in morphology and size. Proteomic analysis of AOs involving iPSC-derived AT2 cells and primary lung fibroblasts revealed mitochondrial dysfunction in HPS1 patient-specific alveolar epithelial cells. Further, giant lamellar bodies were recapitulated in patient-specific AT2 cells.ConclusionsThe HPS1 patient-specific iPSCs and their gene-corrected counterparts generated in this study could be a new research tool for understanding the pathogenesis of HPSIP caused by HPS1 deficiency in humans.

| S-EPMC8570015 | biostudies-literature

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

| PRJNA1168925 | ENA

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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