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

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.

• 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
• Journal: Cell stem cell (Cell Stem Cell) Vol. 13 Issue 6 Pg. 691-705 (Dec 05 2013) ISSN: 1875-9777 [Electronic] United States
• PMID: 24315443 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers
• Lamin Type A
• Nuclear Proteins
• Protein Precursors
• prelamin A

Topics

• Adult
• Age of Onset
• Aged
• Aged, 80 and over
• Aging (pathology)
• Animals
• Biomarkers (metabolism)
• Cell Differentiation
• Cellular Reprogramming
• Cellular Senescence
• Child
• Dopaminergic Neurons (metabolism, pathology, transplantation, ultrastructure)
• Fibroblasts (metabolism)
• Humans
• Induced Pluripotent Stem Cells (metabolism)
• Lamin Type A
• Mesencephalon (pathology)
• Mice
• Middle Aged
• Models, Biological
• Nuclear Proteins (metabolism)
• Parkinson Disease (pathology)
• Phenotype
• Protein Precursors (metabolism)
• Tissue Donors