@article{0d659c7763844c1a87aff04f676f7fee,
title = "Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects",
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.}",
note = "Funding Information: We thank Ken Diffenderfer and the Salk STEM core facility for technical support with iPSC generation; Caz O{\textquoteright}Connor and Conor Fitzpatrick for FACSorting; and Lynne Moore, Neal Nathan, Eric Konkel, T.J. Eames, and Kim McIntyre for technical support. We thank the DNA and Cell Bank of ICM in Paris for fibroblast banking; Leah Boyer, Carol M. Marchetto, Andres Paucar, Alexandra Durr, Olga Corti, and Alexis Brice for their contribution to fibroblast collection; Peter Davies for antibodies; and Mary Lynn Gage for editorial comments. Human prefrontal cortex samples were provided by the NICHD Brain Bank. The study was supported by the G. Harold & Leila Y. Mathers Charitable Foundation, the JPB Foundation, the Leona M. and Harry B. Helmsley Charitable Trust grant #2012-PG-MED002, Annette Merle-Smith, CIRM (TR2-01778), the German Federal Ministry of Education and Research (BMBF, FKZ: 1315874, #01GN0979), the Bavarian State of Ministry of Education, Science and the Arts in the framework ForIPS, and the Glenn Foundation Center For Aging Research. Funding Information: We thank Ken Diffenderfer and the Salk STEM core facility for technical support with iPSC generation; Caz O''Connor and Conor Fitzpatrick for FACSorting; and Lynne Moore, Neal Nathan, Eric Konkel, T.J. Eames, and Kim McIntyre for technical support. We thank the DNA and Cell Bank of ICM in Paris for fibroblast banking; Leah Boyer, Carol M. Marchetto, Andres Paucar, Alexandra Durr, Olga Corti, and Alexis Brice for their contribution to fibroblast collection; Peter Davies for antibodies; and Mary Lynn Gage for editorial comments. Human prefrontal cortex samples were provided by the NICHD Brain Bank. The study was supported by the G. Harold & Leila Y. Mathers Charitable Foundation, the JPB Foundation, the Leona M. and Harry B. Helmsley Charitable Trust grant #2012-PG-MED002, Annette Merle-Smith, CIRM (TR2- 01778), the German Federal Ministry of Education and Research (BMBF, FKZ: 1315874, #01GN0979), the Bavarian State of Ministry of Education, Science and the Arts in the framework ForIPS, and the Glenn Foundation Center For Aging Research. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",
year = "2015",
month = dec,
day = "3",
doi = "10.1016/j.stem.2015.09.001",
language = "English (US)",
volume = "17",
pages = "705--718",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "6",
}
