Human iPSC-based Modeling of Late-Onset Disease via Progerin-induced Aging

By Justine D. Miller, Yosif M. Ganat, Sarah Kishinevsky, Robert L. Bowman, Becky Liu, Edmund Y. Tu, P. Mandal, Elsa Vera, Jae-won Shim, Sonja Kriks and 7 more. Cell Stem Cell, 2013

750 citations recorded by the source corpus.

Summary 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/85646629670007abee7746a9dfe241cf52809acf

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Citations in the corpus

Brain organoids: advances, applications and challenges (2019, background): “One such strategy for inducing aging-related features in human iPSC-derived organoids, used to model PD, involves the expression of progerin, a truncated form of lamin A associated with premature aging (Miller et al., 2013).”
Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects (2015, positive): “…et al., 2011), reactive oxygen species (Mertens et al., 2013a; Nguyen et al., 2011; Reinhardt et al., 2013), or overexpression of disease- or aging-related mutant proteins to accelerate pathological processes in these otherwise rejuvenated neuronal cells (Koch et al., 2012; Miller et al., 2013).”
Mitophagy and Alzheimer’s disease: cellular and molecular mechanisms (2017, methodology): “The neuronal expression of progerin, a truncated form of lamin A which is defective in Hutchinson-Gilford progeria syndrome [102], and the direct reprogramming of fibroblasts are two recent approaches that have been used to impart a more ‘aged’ cellular phenotype.”