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

doi:10.1016/j.stem.2013.11.006

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

Neurology

Research output: Contribution to journal › Article › peer-review

579 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 language	English (US)
Pages (from-to)	691-705
Number of pages	15
Journal	Cell stem cell
Volume	13
Issue number	6
DOIs	https://doi.org/10.1016/j.stem.2013.11.006
State	Published - Dec 5 2013

Funding

We thank the K. Eggan lab for retroviral-derived control iPSCs, Philip Manos for modified-RNA technical advice, C. Klein for PD fibroblasts, Yvonne Mica and Elizabeth Calder for general technical advice and data interpretation, Andreina Gonzalez, Tracey Van Kempen, and Vladimir Mudragel for help in preparing electron microscopy samples, the MSKCC genomics core laboratory for RNA-seq, MSKCC Molecular Cytology Core facility for histology slices, and MSKCC Cytogenetics core facility for karyotyping. D.J.R. is a New York Stem Cell Foundation Robertson Investigator. The work was supported in part by Phil and Marcia Rothblum foundation by NINDS contract NS078338 and by a grant from the Tri-Institutional Stem Cell Initiative (Starr Foundation) to L.S., and NIH grants DA08259 and HL098351 to T.A.M. and NS076054 to D.K. J.D.M was supported by an NSF fellowship.

ASJC Scopus subject areas

Genetics
Molecular Medicine
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.stem.2013.11.006

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Miller, J. D., Ganat, Y. M., Kishinevsky, S., Bowman, R. L., Liu, B., Tu, E. Y., Mandal, P. K., Vera, E., Shim, J. W., Kriks, S., Taldone, T., Fusaki, N., Tomishima, M. J., Krainc, D., Milner, T. A., Rossi, D. J., & Studer, L. (2013). Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell stem cell, 13(6), 691-705. https://doi.org/10.1016/j.stem.2013.11.006

@article{b7bd1e3151b14ed6881db86d6e0e97b4,

title = "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.",

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

note = "Funding Information: We thank the K. Eggan lab for retroviral-derived control iPSCs, Philip Manos for modified-RNA technical advice, C. Klein for PD fibroblasts, Yvonne Mica and Elizabeth Calder for general technical advice and data interpretation, Andreina Gonzalez, Tracey Van Kempen, and Vladimir Mudragel for help in preparing electron microscopy samples, the MSKCC genomics core laboratory for RNA-seq, MSKCC Molecular Cytology Core facility for histology slices, and MSKCC Cytogenetics core facility for karyotyping. D.J.R. is a New York Stem Cell Foundation Robertson Investigator. The work was supported in part by Phil and Marcia Rothblum foundation by NINDS contract NS078338 and by a grant from the Tri-Institutional Stem Cell Initiative (Starr Foundation) to L.S., and NIH grants DA08259 and HL098351 to T.A.M. and NS076054 to D.K. J.D.M was supported by an NSF fellowship. ",

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doi = "10.1016/j.stem.2013.11.006",

language = "English (US)",

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T1 - Human iPSC-based modeling of late-onset disease via progerin-induced aging

AU - Miller, Justine D.

AU - Ganat, Yosif M.

AU - Kishinevsky, Sarah

AU - Bowman, Robert L.

AU - Liu, Becky

AU - Tu, Edmund Y.

AU - Mandal, Pankaj K.

AU - Vera, Elsa

AU - Shim, Jae Won

AU - Kriks, Sonja

AU - Taldone, Tony

AU - Fusaki, Noemi

AU - Tomishima, Mark J.

AU - Krainc, Dimitri

AU - Milner, Teresa A.

AU - Rossi, Derrick J.

AU - Studer, Lorenz

N1 - Funding Information: We thank the K. Eggan lab for retroviral-derived control iPSCs, Philip Manos for modified-RNA technical advice, C. Klein for PD fibroblasts, Yvonne Mica and Elizabeth Calder for general technical advice and data interpretation, Andreina Gonzalez, Tracey Van Kempen, and Vladimir Mudragel for help in preparing electron microscopy samples, the MSKCC genomics core laboratory for RNA-seq, MSKCC Molecular Cytology Core facility for histology slices, and MSKCC Cytogenetics core facility for karyotyping. D.J.R. is a New York Stem Cell Foundation Robertson Investigator. The work was supported in part by Phil and Marcia Rothblum foundation by NINDS contract NS078338 and by a grant from the Tri-Institutional Stem Cell Initiative (Starr Foundation) to L.S., and NIH grants DA08259 and HL098351 to T.A.M. and NS076054 to D.K. J.D.M was supported by an NSF fellowship.

PY - 2013/12/5

Y1 - 2013/12/5

N2 - 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.

AB - 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.

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JO - Cell stem cell

JF - Cell stem cell

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ER -

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

Abstract

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UN SDGs

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