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

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE121999 | GEO | 2019/06/25

REPOSITORIES: GEO

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

| PRJNA502562 | ENA

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

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

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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

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)

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Project description:Hermansky-Pudlak syndrome type2

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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

Hermansky-Pudlak syndrome: Mutation update.

Project description:Hermansky-Pudlak syndrome (HPS) is a group of 10 autosomal recessive multisystem disorders, each defined by the deficiency of a specific gene. HPS-associated genes encode components of four ubiquitously expressed protein complexes: Adaptor protein-3 (AP-3) and biogenesis of lysosome-related organelles complex-1 (BLOC-1) through -3. All individuals with HPS exhibit albinism and a bleeding diathesis; additional features occur depending on the defective protein complex. Pulmonary fibrosis is associated with AP-3 and BLOC-3 deficiency, immunodeficiency with AP-3 defects, and gastrointestinal symptoms are more prevalent and severe in BLOC-3 deficiency. Therefore, identification of the HPS subtype is valuable for prognosis, clinical management, and treatment options. The prevalence of HPS is estimated at 1-9 per 1,000,000. Here we summarize 264 reported and novel variants in 10 HPS genes and estimate that ~333 Puerto Rican HPS subjects and ~385 with other ethnicities are reported to date. We provide pathogenicity predictions for missense and splice site variants and list variants with high minor allele frequencies. Current cellular and clinical aspects of HPS are also summarized. This review can serve as a manifest for molecular diagnostics and genetic counseling aspects of HPS.

| S-EPMC8175076 | biostudies-literature

Defective AP-3-dependent VAMP8 trafficking impairs Weibel-Palade body exocytosis in Hermansky-Pudlak Syndrome type 2 blood outgrowth endothelial cells.

Project description:Weibel-Palade bodies (WPBs) are endothelial secretory organelles that contain VWF, P-selectin and CD63. Release of VWF from WPBs is crucial for platelet adhesion during primary hemostasis. Endosomal trafficking of proteins like CD63 to WPBs during maturation is dependent on the AP-3 complex. Mutations in the AP3B1 gene, which encodes the AP-3 β1 subunit, result in Hermansky-Pudlak syndrome 2 (HPS-2), a rare genetic disorder that leads to neutropenia and a mild bleeding diathesis. This is caused by abnormal granule formation in neutrophils and platelets due to defects in trafficking of cargo to secretory organelles. The impact of these defects on the secretory pathway of the endothelium is largely unknown. In this study we have investigated the role of AP-3-dependent mechanisms in trafficking of proteins during WPB maturation in endothelial cells. An ex vivo patient-derived endothelial model of HPS-2 was established using blood outgrowth endothelial cells (BOECs) that were isolated from an HPS-2 patient with compound heterozygous mutations in AP3B1. HPS-2 BOECs and CRISPR/Cas9-engineered AP3B1-/- BOECs contain WPBs that are entirely devoid of CD63, indicative of disrupted endosomal trafficking to the WPB membrane. HPS-2 BOECs have impaired Ca2+- and cAMP-mediated WPB exocytosis. Whole proteome analysis of HPS-2 BOECs revealed that apart from AP-3β1 also the AP-3µ1 subunit and the v-SNARE VAMP8 were depleted. Stimulus-induced VWF secretion was impaired in CRISPR/Cas9-engineered VAMP8-/- BOECs. Our data show that defects in AP-3 dependent maturation of WPBs impairs WPB exocytosis by affecting the recruitment of the WPB-localized member of the SNARE fusion machinery VAMP8.

2019-01-31 | PXD011294 | Pride

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