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Cell Stem Cell. 2013 Dec 5;13(6):691-705. doi: 10.1016/j.stem.2013.11.006.

Human iPSC-based modeling of late-onset disease via progerin-induced aging.

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  • 1The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA; Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA; Gerstner Sloan-Kettering Graduate School, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA.

Abstract

Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) resets their identity back to an embryonic age and, thus, presents a significant hurdle for modeling late-onset disorders. In this study, we describe a strategy for inducing aging-related features in human iPSC-derived lineages and apply it to the modeling of Parkinson's disease (PD). Our approach involves expression of progerin, a truncated form of lamin A associated with premature aging. We found that expression of progerin in iPSC-derived fibroblasts and neurons induces multiple aging-related markers and characteristics, including dopamine-specific phenotypes such as neuromelanin accumulation. Induced aging in PD iPSC-derived dopamine neurons revealed disease phenotypes that require both aging and genetic susceptibility, such as pronounced dendrite degeneration, progressive loss of tyrosine hydroxylase (TH) expression, and enlarged mitochondria or Lewy-body-precursor inclusions. Thus, our study suggests that progerin-induced aging can be used to reveal late-onset age-related disease features in hiPSC-based disease models.

Copyright © 2013 Elsevier Inc. All rights reserved.

PMID:
24315443
[PubMed - indexed for MEDLINE]
PMCID:
PMC4153390
Free PMC Article
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