Induced Pluripotent Stem Cell Modeling of Multisystemic, Hereditary Transthyretin Amyloidosis

Overview

Journal Stem Cell Reports

Publisher Cell Press

Specialty Cell Biology

Date 2013 Nov 29

PMID 24286032

Citations 24

Authors

Amy Leung

Shirley K Nah

Whitney Reid

Atsushi Ebata

Clarissa M Koch

Stefano Monti

Joseph C Genereux

R Luke Wiseman

Benjamin Wolozin

Lawreen H Connors

John L Berk

David C Seldin

Gustavo Mostoslavsky

Darrell N Kotton

George J Murphy

Affiliations

Soon will be listed here.

Abstract

Familial transthyretin amyloidosis (ATTR) is an autosomal-dominant protein-folding disorder caused by over 100 distinct mutations in the transthyretin (TTR) gene. In ATTR, protein secreted from the liver aggregates and forms fibrils in target organs, chiefly the heart and peripheral nervous system, highlighting the need for a model capable of recapitulating the multisystem complexity of this clinically variable disease. Here, we describe the directed differentiation of ATTR patient-specific iPSCs into hepatocytes that produce mutant TTR, and the cardiomyocytes and neurons normally targeted in the disease. We demonstrate that iPSC-derived neuronal and cardiac cells display oxidative stress and an increased level of cell death when exposed to mutant TTR produced by the patient-matched iPSC-derived hepatocytes, recapitulating essential aspects of the disease in vitro. Furthermore, small molecule stabilizers of TTR show efficacy in this model, validating this iPSC-based, patient-specific in vitro system as a platform for testing therapeutic strategies.

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