Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects.
Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects.
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DOI：
10.1016/j.stem.2015.09.001
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发表时间：
2015-12-03
期刊：
影响因子：
23.9
通讯作者：
Gage FH
中科院分区：
文献类型：
--
作者：
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
衰老是许多人类疾病的主要风险因素，并且体外生成人类神经元是用于建模与衰老相关的脑疾病的有吸引力的方法。然而，在分化的人类神经元中建模衰老已被证明具有挑战性。我们从不同年龄段的人类供体中产生了神经元，无论是通过基于iPSC的重编程和分化，还是通过直接转化为诱导神经元（iN）。虽然iPSC和衍生的神经元没有保留与衰老相关的基因特征，但iNs显示出年龄特异性转录谱，并揭示了核转运受体RanBP17的年龄相关性降低。我们在供体成纤维细胞和相应的iN中检测到核质区室化（NCC）的年龄依赖性损失，并发现减少的RanBP17损害年轻细胞中的NCC，而iPSC复壮恢复老年细胞中的NCC。这些结果表明，iN保留了重要的衰老相关特征，从而允许体外衰老过程的建模，并且它们将受损的NCC确定为人类衰老的重要因素。Mertens及其同事比较了人类成纤维细胞，诱导神经元（iN），iPSC，iPSC衍生的神经元和来自广泛老年供体的大脑样本的转录组，发现iN保留了供体衰老特征，而iPSC则恢复了活力。RanBP17在衰老过程中持续降低，导致老年人细胞核质区室化受损。
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. In Brief Mertens and colleagues compare transcriptomes of human fibroblasts, induced neurons (iNs), iPSCs, iPSC-derived neurons, and brain samples from a broad range of aged donors, finding that iNs retain donor aging signatures, while iPSCs are rejuvenated. RanBP17 was consistently decreased during aging, leading to compromised nucleocytoplasmic compartmentalization in aged human cells.
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影响因子：
64.8
作者：
Israel, Mason A.;Yuan, Shauna H.;Bardy, Cedric;Reyna, Sol M.;Mu, Yangling;Herrera, Cheryl;Hefferan, Michael P.;Van Gorp, Sebastiaan;Nazor, Kristopher L.;Boscolo, Francesca S.;Carson, Christian T.;Laurent, Louise C.;Marsala, Martin;Gage, Fred H.;Remes, Anne M.;Koo, Edward H.;Goldstein, Lawrence S. B.
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影响因子：
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作者：
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