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

• Published in: Cell stem cell Vol. 13; no. 6; pp. 691 - 705
• Main Authors: Miller, Justine D., Ganat, Yosif M., Kishinevsky, Sarah, Bowman, Robert L., Liu, Becky, Tu, Edmund Y., Mandal, Pankaj K., Vera, Elsa, Shim, Jae-won, Kriks, Sonja, Taldone, Tony, Fusaki, Noemi, Tomishima, Mark J., Krainc, Dimitri, Milner, Teresa A., Rossi, Derrick J., Studer, Lorenz
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.12.2013
• Subjects: Adult; Age of Onset; Aged; Aged, 80 and over; Aging - pathology; Animals; Biomarkers - metabolism; Cell Differentiation; Cellular Reprogramming; Cellular Senescence; Child; disease models; dopamine; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Dopaminergic Neurons - transplantation; Dopaminergic Neurons - ultrastructure; fibroblasts; Fibroblasts - metabolism; Humans; induced pluripotent stem cells; Induced Pluripotent Stem Cells - metabolism; Lamin Type A; Mesencephalon - pathology; Mice; Middle Aged; mitochondria; Models, Biological; neurons; Nuclear Proteins - metabolism; Parkinson disease; Parkinson Disease - pathology; Phenotype; Protein Precursors - metabolism; somatic cells; Tissue Donors; tyrosine
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2013.11.006

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. [Display omitted] •Reprogramming rejuvenates old donor fibroblasts by erasing age-related markers•Differentiation of old donor iPSCs is not sufficient to trigger memory of age•Progerin induces age-associated phenotypes in iPSC-derived fibroblasts and neurons•Progerin reveals late-onset disease phenotypes in iPSC-based models of genetic PD The induction of aging-related features in human iPS-derived cells through expression of progerin addresses one of the major limitations of human iPS-based disease modeling and enables analysis of late-onset phenotypes in conditions such as Parkinson’s disease.