Human iPSC-Based Modeling of Late-Onset Disease via Progerin-Induced Aging

• DOI: 10.1016/j.stem.2013.11.006
• Publication Date: 2013-12-05T16:35:32Z
• Authors: 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
• Keywords: Adult; Aging; Induced Pluripotent Stem Cells; Models, Biological; Mice; 03 medical and health sciences; Mesencephalon; Genetics; Animals; Humans; Age of Onset; Child; Cellular Senescence; Aged; Aged, 80 and over; 0303 health sciences; Dopaminergic Neurons; Cell Differentiation; Cell Biology; Fibroblasts; Middle Aged; Cellular Reprogramming; Lamin Type A; Molecular Medicine; Biomarkers

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.