Induced pluripotent stem cells model personalized variations in XXXX resulting from a1-antitrypsin deficiency.

@entity1 @entity74 @entity99 @entity409
UNASSIGNED: In the classical form of a1-antitrypsin deficiency (ATD), aberrant intracellular accumulation of misfolded mutant a1-antitrypsin Z (ATZ) in hepatocytes causes @entity99 by a gain-of-function, "proteotoxic" mechanism. Whereas some ATD @entity1 develop @entity409 ( @entity409 ) that necessitates liver transplantation, others with the same @entity74 completely escape this clinical phenotype. We investigated whether induced pluripotent stem cells (iPSCs) from ATD individuals with or without @entity409 could model these personalized variations in @entity99 phenotypes. @entity1 -specific iPSCs were generated from ATD @entity1 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 @entity409 @entity1 , compared to those from no @entity409 @entity1 . 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 @entity409 . CONCLUSION: These results provide definitive validation that iHeps model the individual disease phenotypes of ATD @entity1 with more rapid degradation of misfolded ATZ and lack of globular inclusions in cells from @entity1 who have escaped @entity409 . 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. (Hepatology 2015).
