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Hepatology. 2015 Jul;62(1):147-57. doi: 10.1002/hep.27753. Epub 2015 Apr 13.

Induced pluripotent stem cells model personalized variations in liver disease resulting from α1-antitrypsin deficiency.

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Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA.
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA.
McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Department of Medicine, Medical University of South Carolina, Charleston, SC.
Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA.
Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden.
Department of Medicine, Albert Einstein College of Medicine, New York, NY.
Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh.


In the classical form of α1-antitrypsin deficiency (ATD), aberrant intracellular accumulation of misfolded mutant α1-antitrypsin Z (ATZ) in hepatocytes causes hepatic damage by a gain-of-function, "proteotoxic" mechanism. Whereas some ATD patients develop severe liver disease (SLD) that necessitates liver transplantation, others with the same genetic defect completely escape this clinical phenotype. We investigated whether induced pluripotent stem cells (iPSCs) from ATD individuals with or without SLD could model these personalized variations in hepatic disease phenotypes. Patient-specific iPSCs were generated from ATD patients and a control and differentiated into hepatocyte-like cells (iHeps) having many characteristics of hepatocytes. Pulse-chase and endoglycosidase H analysis demonstrate that the iHeps recapitulate the abnormal accumulation and processing of the ATZ molecule, compared to the wild-type AT molecule. Measurements of the fate of intracellular ATZ show a marked delay in the rate of ATZ degradation in iHeps from SLD patients, compared to those from no liver disease patients. Transmission electron microscopy showed dilated rough endoplasmic reticulum in iHeps from all individuals with ATD, not in controls, but globular inclusions that are partially covered with ribosomes were observed only in iHeps from individuals with SLD.


iHeps model the individual disease phenotypes of ATD patients with more rapid degradation of misfolded ATZ and lack of globular inclusions in cells from patients who have escaped liver disease. The results support the concept that "proteostasis" mechanisms, such as intracellular degradation pathways, play a role in observed variations in clinical phenotype and show that iPSCs can potentially be used to facilitate predictions of disease susceptibility for more precise and timely application of therapeutic strategies.

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