Directly converted astrocytes retain the ageing features of the donor fibroblasts and elucidate the astrocytic contribution to human CNS health and disease.
Directly converted astrocytes retain the ageing features of the donor fibroblasts and elucidate the astrocytic contribution to human CNS health and disease.
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DOI：
10.1111/acel.13281
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发表时间：
2021-01
期刊：
影响因子：
7.8
通讯作者：
Ferraiuolo L
中科院分区：
文献类型：
--
作者：
Gatto N;Dos Santos Souza C;Shaw AC;Bell SM;Myszczynska MA;Powers S;Meyer K;Castelli LM;Karyka E;Mortiboys H;Azzouz M;Hautbergue GM;Márkus NM;Shaw PJ;Ferraiuolo L
星形胶质细胞是高度特化的细胞，负责CNS稳态和神经元活动。缺乏能够概括衰老过程中影响星形胶质细胞的功能变化的人类体外系统是研究旨在保护神经元健康的机制和潜在疗法的主要限制。在这里，我们发现，来自儿童或成年成纤维细胞供体的诱导星形胶质细胞显示出与年龄相关的转录差异，并在一系列与年龄相关的特征中功能上存在差异，例如改变的核区室化，核质穿梭特性，氧化应激反应和DNA损伤反应。值得注意的是，我们还显示了诱导神经祖细胞衍生的星形胶质细胞（iNPC-As）在促炎刺激后支持共培养神经元的能力方面的年龄相关差异反应。这些结果表明，iNPC-A是一种可再生的、易于获得的人神经胶质资源，保留了供体成纤维细胞的年龄相关特征，使其成为一种独特且有价值的模型，用于在人CNS健康和疾病中研究人星形胶质细胞随时间的功能。来自不同年龄供体的成纤维细胞的iNPC-A保留了一系列年龄相关特征，如核形态和组织，以及特定的核质穿梭特征和氧化应激反应。此外，在人共培养物中，促炎性损伤后，旧供体来源的iNPC-A对神经元的支持性较低。
Astrocytes are highly specialised cells, responsible for CNS homeostasis and neuronal activity. Lack of human in vitro systems able to recapitulate the functional changes affecting astrocytes during ageing represents a major limitation to studying mechanisms and potential therapies aiming to preserve neuronal health. Here, we show that induced astrocytes from fibroblasts donors in their childhood or adulthood display age‐related transcriptional differences and functionally diverge in a spectrum of age‐associated features, such as altered nuclear compartmentalisation, nucleocytoplasmic shuttling properties, oxidative stress response and DNA damage response. Remarkably, we also show an age‐related differential response of induced neural progenitor cells derived astrocytes (iNPC‐As) in their ability to support neurons in co‐culture upon pro‐inflammatory stimuli. These results show that iNPC‐As are a renewable, readily available resource of human glia that retain the age‐related features of the donor fibroblasts, making them a unique and valuable model to interrogate human astrocyte function over time in human CNS health and disease. iNPC‐As from fibroblasts isolated from donors of different ages retain a spectrum of age‐associated features, such as nuclear morphology and organization, as well as specific nucleo‐cytoplasm shuttling characteristics and oxidative stress response. Moreover, old donor‐derived iNPCs‐As are less supportive to neurons after pro‐inflammatory insult in human co‐culture.
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影响因子：
5.3
作者：
Ben Haim L;Carrillo-de Sauvage MA;Ceyzériat K;Escartin C
通讯作者：
Escartin C
影响因子：
16.6
作者：
Du, Zhong-Wei;Chen, Hong;Liu, Huisheng;Lu, Jianfeng;Qian, Kun;Huang, CindyTzu-Ling;Zhong, Xiaofen;Fan, Frank;Zhang, Su-Chun
通讯作者：
Zhang, Su-Chun
影响因子：
5.3
作者：
Ciccarone, Fabio;Tagliatesta, Stefano;Zampieri, Michele
通讯作者：
Zampieri, Michele
来自小鼠大脑多个区域的老化星形胶质细胞转录组。
影响因子：
8.8
作者：
Boisvert MM;Erikson GA;Shokhirev MN;Allen NJ
通讯作者：
Allen NJ
影响因子：
16.2
作者：
Gasset-Rosa F;Chillon-Marinas C;Goginashvili A;Atwal RS;Artates JW;Tabet R;Wheeler VC;Bang AG;Cleveland DW;Lagier-Tourenne C
通讯作者：
Lagier-Tourenne C