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

By J. Mertens, A. Paquola, Manching Ku, Emily M. Hatch, Lena Böhnke, Shauheen Ladjevardi, S. McGrath, Benjamin Campbell, Hyungjun Lee, J. Herdy and 7 more. Cell Stem Cell, 2015

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SUMMARY 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/50ec47a2403bec47b5a1b7656693b117622586f3

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Current Challenges of iPSC-Based Disease Modeling and Therapeutic Implications (2019, background): “An alternative approach would be the direct conversion of somatic cells such as fibroblasts into clinically relevant phenotypic cells such as neurons and cardiomyocytes to preserve the cellular ageing markers and possibly maturation state [111,112].”