ArticleCell reports2022
Human iPSC-hepatocyte modeling of alpha-1 antitrypsin heterozygosity reveals metabolic dysregulation and cellular heterogeneity.
Article in Cell reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 1 of them a synthesis that pooled it.
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Who cites it
15 citing papers in PubMed, 1 synthesis or guideline pooled it, 14 citations in OpenAlex.
- Meta-Analysis: Redefining Liver Disease Risk in Heterozygous Alpha-1 Antitrypsin Deficiency.Alimentary pharmacology & therapeutics · 2026Pooled it
- Integrating CRISPR genome editing with liver organoid and hiPSC-derived microfluidic platforms to model metabolic dysfunction-associated steatotic liver disease.Biochemistry and biophysics reports · 2026Review
- Macrophages orchestrate antiviral defense and epithelial repair in a human iPSC-derived alveolar air-liquid interface.JCI insight · 2026Article
- AT2-intrinsic Z-AAT expression drives conserved inflammatory and proteotoxic stress responses and predisposes to emphysema.bioRxiv : the preprint server for biology · 2026Article
- Z variant heterozygosity in alpha-1 antitrypsin deficiency: disease risk and treatment implications.Orphanet journal of rare diseases · 2026Article
- Gene Editing of Pluripotent Stem Cell-Derived Hepatic Cells for Liver Disease Modeling and Therapeutic Development.Biomolecules & therapeutics · 2026Review
- A compact base editor rescues AATD-associated liver and lung disease in mouse models.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Rationale and Design of the Alpha-1 Biomarkers Consortium Study.Chronic obstructive pulmonary diseases (Miami, Fla.) · 2025Article
- Altered polyadenylation site usage in SERPINA1 3'UTR in response to cellular stress affects A1AT protein expression.Scientific reports · 2025Article
- Experimental Models to Investigate PNPLA3 in Liver Steatosis.Liver international : official journal of the International Association for the Study of the Liver · 2025Review
- Disturbed function of TBL1X has a differential effect on T3-regulated gene expression in two human liver cell models.European thyroid journal · 2024Article
- Transient growth factor expression via mRNA in lipid nanoparticles promotes hepatocyte cell therapy in mice.Nature communications · 2024Article
- Quantitative Lipid Profiling Reveals Major Differences between Liver Organoids with Normal Pi*M and Deficient Pi*Z Variants of Alpha-1-antitrypsin.International journal of molecular sciences · 2023Article
- Fibrosis-Related Gene Profiling in Liver Biopsies of PiZZ α1-Antitrypsin Children with Different Clinical Courses.International journal of molecular sciences · 2023Article
- Detection of lineage-reprogramming efficiency of tumor cells in a 3D-printed liver-on-a-chip model.Theranostics · 2023Article
Corrections and comments
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Authors and funding
19 authors at 5 institutions in 3 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.