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

被引：522

作者：

Mertens, Jerome ^{[1
]}

Paquola, Apua C. M. ^{[1
]}

Ku, Manching ^{[2
]}

Hatch, Emily ^{[3
]}

Boehnke, Lena ^{[1
]}

Ladjevardi, Shauheen ^{[1
]}

McGrath, Sean ^{[1
]}

Campbell, Benjamin ^{[1
]}

Lee, Hyungjun ^{[1
]}

Herdy, Joseph R. ^{[1
]}

Goncalves, J. Tiago ^{[1
]}

Toda, Tomohisa ^{[1
]}

Kim, Yongsung ^{[1
]}

Winkler, Juergen ^{[4
]}

Yao, Jun ^{[5
]}

Hetzer, Martin W. ^{[3
]}

Gage, Fred H. ^{[1
]}

机构：

[1] Salk Inst Biol Studies, Genet Lab, La Jolla, CA 92037 USA

[2] Salk Inst Biol Studies, Next Generat Sequencing Core, La Jolla, CA 92037 USA

[3] Salk Inst Biol Studies, Mol & Cell Biol Lab, La Jolla, CA 92037 USA

[4] Univ Erlangen Nurnberg, Dept Mol Neurol, D-91054 Erlangen, Germany

[5] Tsinghua Univ, Tsinghua Peking Joint Ctr Life Sci, Sch Life Sci, McGovern Inst Brain,State Key Lab Membrane Biol, Beijing 100084, Peoples R China

来源：

CELL STEM CELL | 2015年 / 17卷 / 06期

关键词：

PLURIPOTENT STEM-CELLS; HUMAN FIBROBLASTS; HIGHLY EFFICIENT; GENE-REGULATION; DNA-DAMAGE; IDENTIFICATION; REJUVENATION; PROGERIA; DISEASE; CONVERSION;

D O I：

10.1016/j.stem.2015.09.001

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Aging is amajor 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.

引用

页码：705 / 718

页数：14

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