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

Justine D. Miller, Yosif M. Ganat, Sarah Kishinevsky, Robert L. Bowman, Becky Liu, Edmund Y. Tu, Pankaj K. Mandal, Elsa Vera, Jae Won Shim, Sonja Kriks, Tony Taldone, Noemi Fusaki, Mark J. Tomishima, Dimitri Krainc, Teresa A. Milner, Derrick J. Rossi, Lorenz Studer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

400 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)691-705
Number of pages15
JournalCell stem cell
Volume13
Issue number6
DOIs
StatePublished - Dec 5 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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