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Induced pluripotent stem cell modeling of multisystemic, hereditary transthyretin amyloidosis

Academic Article
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Overview

authors

  • Leung, A.
  • Nah, S. K.
  • Reid, W.
  • Ebata, A.
  • Koch, C. M.
  • Monti, S.
  • Genereux, J. C.
  • Wiseman, R. Luke
  • Wolozin, B.
  • Connors, L. H.
  • Berk, J. L.
  • Seldin, D. C.
  • Mostoslavsky, G.
  • Kotton, D. N.
  • Murphy, G. J.

publication date

  • 2013

journal

  • Stem Cell Reports  Journal

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.

subject areas

  • Adult
  • Amyloid Neuropathies, Familial
  • Cell Differentiation
  • Cells, Cultured
  • Female
  • Hepatocytes
  • Humans
  • Induced Pluripotent Stem Cells
  • Mutation
  • Myocytes, Cardiac
  • Neurons
  • Oxidative Stress
  • Prealbumin
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Identity

PubMed Central ID

  • PMC3841264

International Standard Serial Number (ISSN)

  • 2213-6711 (Electronic) 2213-6711 (Linking)

Digital Object Identifier (DOI)

  • 10.1016/j.stemcr.2013.10.003

PubMed ID

  • 24286032
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Additional Document Info

start page

  • 451

end page

  • 463

volume

  • 1

issue

  • 5

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