Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects

Jerome Mertens; Apuã C.M. Paquola; Manching Ku; Emily Hatch; Lena Böhnke; Shauheen Ladjevardi; Sean McGrath; Benjamin Campbell; Hyungjun Lee; Joseph R. Herdy; J. Tiago Gonçalves; Tomohisa Toda; Yongsung Kim; Jürgen Winkler; Jun Yao; Martin W. Hetzer; Fred H. Gage

doi:10.1016/j.stem.2015.09.001

Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects

Jerome Mertens, Apuã C.M. Paquola, Manching Ku, Emily Hatch, Lena Böhnke, Shauheen Ladjevardi, Sean McGrath, Benjamin Campbell, Hyungjun Lee, Joseph R. Herdy, J. Tiago Gonçalves, Tomohisa Toda, Yongsung Kim, Jürgen Winkler, Jun Yao, Martin W. Hetzer, Fred H. Gage

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

486 Scopus citations

Abstract

Aging is a major risk factor for many human diseases, and in vitro generation of human neurons is an attractive approach for modeling aging-related brain disorders. However, modeling aging in differentiated human neurons has proved challenging. We generated neurons from human donors across a broad range of ages, either by iPSC-based reprogramming and differentiation or by direct conversion into induced neurons (iNs). While iPSCs and derived neurons did not retain aging-associated gene signatures, iNs displayed age-specific transcriptional profiles and revealed age-associated decreases in the nuclear transport receptor RanBP17. We detected an age-dependent loss of nucleocytoplasmic compartmentalization (NCC) in donor fibroblasts and corresponding iNs and found that reduced RanBP17 impaired NCC in young cells, while iPSC rejuvenation restored NCC in aged cells. These results show that iNs retain important aging-related signatures, thus allowing modeling of the aging process in vitro, and they identify impaired NCC as an important factor in human aging.

Original language	English (US)
Pages (from-to)	705-718
Number of pages	14
Journal	Cell Stem Cell
Volume	17
Issue number	6
DOIs	https://doi.org/10.1016/j.stem.2015.09.001
State	Published - Dec 3 2015
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

UN SDGs

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

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10.1016/j.stem.2015.09.001

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Mertens, J., Paquola, A. C. M., Ku, M., Hatch, E., Böhnke, L., Ladjevardi, S., McGrath, S., Campbell, B., Lee, H., Herdy, J. R., Gonçalves, J. T., Toda, T., Kim, Y., Winkler, J., Yao, J., Hetzer, M. W., & Gage, F. H. (2015). Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects. Cell Stem Cell, 17(6), 705-718. https://doi.org/10.1016/j.stem.2015.09.001

Mertens, J, Paquola, ACM, Ku, M, Hatch, E, Böhnke, L, Ladjevardi, S, McGrath, S, Campbell, B, Lee, H, Herdy, JR, Gonçalves, JT, Toda, T, Kim, Y, Winkler, J, Yao, J, Hetzer, MW & Gage, FH 2015, 'Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects', Cell Stem Cell, vol. 17, no. 6, pp. 705-718. https://doi.org/10.1016/j.stem.2015.09.001

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abstract = "Aging is a major risk factor for many human diseases, and in vitro generation of human neurons is an attractive approach for modeling aging-related brain disorders. However, modeling aging in differentiated human neurons has proved challenging. We generated neurons from human donors across a broad range of ages, either by iPSC-based reprogramming and differentiation or by direct conversion into induced neurons (iNs). While iPSCs and derived neurons did not retain aging-associated gene signatures, iNs displayed age-specific transcriptional profiles and revealed age-associated decreases in the nuclear transport receptor RanBP17. We detected an age-dependent loss of nucleocytoplasmic compartmentalization (NCC) in donor fibroblasts and corresponding iNs and found that reduced RanBP17 impaired NCC in young cells, while iPSC rejuvenation restored NCC in aged cells. These results show that iNs retain important aging-related signatures, thus allowing modeling of the aging process in vitro, and they identify impaired NCC as an important factor in human aging.",

author = "Jerome Mertens and Paquola, {Apu{\~a} C.M.} and Manching Ku and Emily Hatch and Lena B{\"o}hnke and Shauheen Ladjevardi and Sean McGrath and Benjamin Campbell and Hyungjun Lee and Herdy, {Joseph R.} and Gon{\c c}alves, {J. Tiago} and Tomohisa Toda and Yongsung Kim and J{\"u}rgen Winkler and Jun Yao and Hetzer, {Martin W.} and Gage, {Fred H.}",

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AU - Paquola, Apuã C.M.

AU - Ku, Manching

AU - Hatch, Emily

AU - Böhnke, Lena

AU - Ladjevardi, Shauheen

AU - McGrath, Sean

AU - Campbell, Benjamin

AU - Lee, Hyungjun

AU - Herdy, Joseph R.

AU - Gonçalves, J. Tiago

AU - Toda, Tomohisa

AU - Kim, Yongsung

AU - Winkler, Jürgen

AU - Yao, Jun

AU - Hetzer, Martin W.

AU - Gage, Fred H.

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N2 - Aging is a major risk factor for many human diseases, and in vitro generation of human neurons is an attractive approach for modeling aging-related brain disorders. However, modeling aging in differentiated human neurons has proved challenging. We generated neurons from human donors across a broad range of ages, either by iPSC-based reprogramming and differentiation or by direct conversion into induced neurons (iNs). While iPSCs and derived neurons did not retain aging-associated gene signatures, iNs displayed age-specific transcriptional profiles and revealed age-associated decreases in the nuclear transport receptor RanBP17. We detected an age-dependent loss of nucleocytoplasmic compartmentalization (NCC) in donor fibroblasts and corresponding iNs and found that reduced RanBP17 impaired NCC in young cells, while iPSC rejuvenation restored NCC in aged cells. These results show that iNs retain important aging-related signatures, thus allowing modeling of the aging process in vitro, and they identify impaired NCC as an important factor in human aging.

AB - Aging is a major risk factor for many human diseases, and in vitro generation of human neurons is an attractive approach for modeling aging-related brain disorders. However, modeling aging in differentiated human neurons has proved challenging. We generated neurons from human donors across a broad range of ages, either by iPSC-based reprogramming and differentiation or by direct conversion into induced neurons (iNs). While iPSCs and derived neurons did not retain aging-associated gene signatures, iNs displayed age-specific transcriptional profiles and revealed age-associated decreases in the nuclear transport receptor RanBP17. We detected an age-dependent loss of nucleocytoplasmic compartmentalization (NCC) in donor fibroblasts and corresponding iNs and found that reduced RanBP17 impaired NCC in young cells, while iPSC rejuvenation restored NCC in aged cells. These results show that iNs retain important aging-related signatures, thus allowing modeling of the aging process in vitro, and they identify impaired NCC as an important factor in human aging.

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Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects

Abstract

ASJC Scopus subject areas

UN SDGs

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