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A Highly Phenotyped Open Access Repository of Alpha-1 Antitrypsin Deficiency Pluripotent Stem Cells

ABSTRACT: We profiled the global transcriptomes of 10 featured AATD-patient specific iPSC that underwent directed differentiation towards a hepatic and lung lineage. We used digital gene expression (DGE), a platform for high-fidelity RNA sequencing, and in addition to differentiated iPSC-derived cell types mentioned above (iHeps and iPSC-Lung progenitors), we also collected RNA from undifferentiated iPSCs and from a panel of primary adult human hepatocytes (PHH) for comparison.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140732 | GEO | 2020/07/27

REPOSITORIES: GEO

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Single cell RNA sequencing of AATD iPSC-derived hepatocytes following Z mutation correction by base-editing

Project description:We performed single cell transcriptomic profiling of cells derived from induced human pluripotent stem cells (iPSCs) using hepatocyte directed differentiation protocol which derived iHeps. We used the alpha-1 antitrypsin deficiency (AATD) iPSC line, PiZZ1. On day 15 of differentiation, we transfected cells with base editors to correct the AATD Z mutation. On day 21 of differentiation, we captured cells for 10x Genomics Single cell capture (V3 protocol). Control cells (MZ and MM stably corrected iHeps) were included in 1 lane, mixed at a ratio of 1:1 and then genotype was identified using the Vartrix Single-Cell Genotyping tool (10X Genomics). Louvain clustering identified 4 major clusters of cells, including a cluster of cells undergoing ER stress. Base editing decreased the number of cells undergoing ER stress.

2022-01-01 | GSE164417 | GEO

Lung microhemorrhage drives macrophage activation and oxidative/inflammatory damage in α-1 antitrypsin deficiency

Project description:Background. Animal models of elastase intratracheal instillation have shown that elastase, unopposed by α-1 antitrypsin (AAT), can induce alveolar hemorrhage with ensuing macrophage inflammation and lung damage. Aim. To identify markers of alveolar hemorrhage and damage using bronchoalveolar lavage (BAL) samples and lung tissue explants from AAT deficient (AATD) subjects. Methods. BAL samples (17 patients, 15 controls) were evaluated for free heme and iron concentrations. Alveolar macrophage (AlvMac) activation patterns were assessed by RNA sequencing and validated in vitro using heme-stimulated monocyte-derived macrophages (MDM). Lung explants (7 patients, 4 controls) were evaluated for iron sequestration patterns, by Prussian blue stain and ferritin immunohistochemistry, and for ferritin iron imaging and elemental analysis by electron microscopy (EM). Tissue oxidative damage was assessed by 8-OHdG immunohistochemistry. Results. BAL showed significantly elevated free heme and iron concentrations at lobar level. BAL macrophage RNA sequencing showed innate proinflammatory activation, consistent with free heme activation. AATD tissue alveolar and interstitial macrophages showed elevated iron and ferritin accumulation in large lysosomes packed with iron oxide cores with degraded ferritin protein cages. AATD explants showed massive oxidative DNA damage in lung epithelial cells and macrophages. Conclusions. Identification of BAL and tissue markers of alveolar hemorrhage, together with the molecular and cellular evidence of macrophage innate pro-inflammatory activation and oxidative damage, consistent with free heme stimulation, provides ex vivo evidence for the pathogenetic role of elastase-induced alveolar hemorrhage AATD emphysema as shown in animal studies.

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A Highly Phenotyped Open Access Repository of Alpha-1 Antitrypsin Deficiency Pluripotent Stem Cells.

Project description:Individuals with the genetic disorder alpha-1 antitrypsin deficiency (AATD) are at risk of developing lung and liver disease. Patient induced pluripotent stem cells (iPSCs) have been found to model features of AATD pathogenesis but only a handful of AATD patient iPSC lines have been published. To capture the significant phenotypic diversity of the patient population, we describe here the establishment and characterization of a curated repository of AATD iPSCs with associated disease-relevant clinical data. To highlight the utility of the repository, we selected a subset of iPSC lines for functional characterization. Selected lines were differentiated to generate both hepatic and lung cell lineages and analyzed by RNA sequencing. In addition, two iPSC lines were targeted using CRISPR/Cas9 editing to accomplish scarless repair. Repository iPSCs are available to investigators for studies of disease pathogenesis and therapeutic discovery.

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Alpha-1 Antitrypsin Deficiency Liver Disease, Mutational Homogeneity Modulated by Epigenetic Heterogeneity With Links to Obesity

Project description:Alpha-1 antitrypsin deficiency (AATD) liver disease is characterized by marked heterogeneity in presentation and progression, despite a common underlying gene mutation, strongly suggesting the involvement of other genetic and/or epigenetic modifiers. Variation in clinical phenotype has added to the challenge of detection, diagnosis, and testing of new therapies in patients with AATD. We examined the contribution of DNA methylation (5-methylcytosine [5mC]) to AATD liver disease heterogeneity because 5mC responds to environmental and genetic cues and its deregulation is a major driver of liver disease. Using liver biopsies from adults with early-stage AATD and the ZZ genotype, genome-wide 5mC patterns were interrogated. We compared DNA methylation among patients with early AATD, and among patients with normal liver, cirrhosis, and hepatocellular carcinoma derived from multiple etiologic exposures, and linked patient clinical/demographic features. Global analysis revealed significant genomic hypomethylation in AATD liver-impacting genes related to liver cancer, cell cycle, and fibrosis, as well as key regulatory molecules influencing growth, migration, and immune function. Further analysis indicated that 5mC changes are localized, with hypermethylation occurring within a background of genome-wide 5mC loss and with patients with AATD manifesting distinct epigenetic landscapes despite their mutational homogeneity. By integrating clinical data with 5mC landscapes, we observed that CpGs differentially methylated among patients with AATD disease are linked to hallmark clinical features of AATD (e.g., hepatocyte degeneration and polymer accumulation) and further reveal links to well-known sex-specific effects of liver disease progression. Conclusion: Our data reveal molecular epigenetic signatures within this mutationally homogeneous group that point to ways to stratify patients for liver disease risk.

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Modeling of Alpha-1 Antitrypsin Deficiency with Syngeneic Human iPSC-Hepatocytes Reveals Metabolic Dysfunction and Cellular Heterogeneity in PiMZ and PiZZ Hepatic Cells (scRNA-Seq)

Project description:Individuals homozygous for the "Z" mutation in alpha-1 antitrypsin deficiency are known to be at increased risk for liver disease. It has also become clear that some degree of risk is similarly conferred by the heterozygous state. A lack of model systems that recapitulate heterozygosity in human hepatocytes has limited the ability to study the impact of a single Z alpha-1 antitrypsin (ZAAT) allele on hepatocyte biology. Here, we describe the derivation of syngeneic induced pluripotent stem cells (iPSCs) engineered to determine the effects of ZAAT heterozygosity in iPSC-hepatocytes (iHeps). We find that heterozygous MZ iHeps exhibit an intermediate disease phenotype and share with ZZ iHeps alterations in AAT protein processing and downstream perturbations including altered endoplasmic reticulum (ER) and mitochondrial morphology, reduced mitochondrial respiration, and branch-specific activation of the unfolded protein response in cell subpopulations. Our model of MZ heterozygosity thus provides evidence that a single Z allele is sufficient to disrupt hepatocyte homeostatic function.

2022-12-06 | GSE198234 | GEO

Comprehensive characterization of hepatic inflammatory changes in a mouse model of alpha-1 antitrypsin deficiency

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2023-03-19 | GSE206619 | GEO

A Highly Phenotyped Open Access Repository of Alpha-1 Antitrypsin Deficiency Pluripotent Stem Cells

Project description:A Highly Phenotyped Open Access Repository of Alpha-1 Antitrypsin Deficiency Pluripotent Stem Cells

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Global transcriptomic analysis of hepatocyte cells infected with Ebola virus (EBOV)

Project description:We performed transcriptomic analysis of a Ebola virus (EBOV) infected hepatocyte cells. We utilized primary human hepatocytes (PHHs), iPSC-derived hepatocytes (iHeps), and immortalized hepatocarcinoma cell line Huh7 cells. Cells were infected with a multiplicity of infection of 10 and harvested after 1 day. Corresponding Mock infected samples were also included in this study.

2022-09-01 | GSE184638 | GEO

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Project description:in situ proteomic analysis (combining laser microdissection of hepatocytes and mass spectrometry analysis) on formalin-fixed paraffin-embedded (FFPE) human liver tissues of 4 ZZ-Alpha 1-Antitrypsin Deficiency (AATD) pediatric patients and 4 ZZ-AATD adult patients that underwent liver transplantation versus 3 WT individuals infants and 4 adults, and compared proteins differentially expressed in ZZ pediatric and in ZZ adult AATD patients.

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