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直接转化的星形胶质细胞保留了供体细胞成纤维细胞的衰老特征,阐明了星形胶质细胞对人类中枢神经系统健康和疾病的贡献。

Directly converted astrocytes retain the ageing features of the donor fibroblasts and elucidate the astrocytic contribution to human CNS health and disease.

机构信息

Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.

The Research institute, Nationwide Children's Hospital, Columbus, OH, USA.

出版信息

Aging Cell. 2021 Jan;20(1):e13281. doi: 10.1111/acel.13281. Epub 2020 Dec 13.

Abstract

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.

摘要

星形胶质细胞是高度特化的细胞,负责中枢神经系统的稳态和神经元活动。缺乏能够重现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治疗方法的主要限制。在这里,我们表明,来自儿童或成年供体的诱导星形胶质细胞表现出与年龄相关的转录差异,并在一系列与年龄相关的特征上表现出功能上的差异,例如核区室化、核质穿梭特性、氧化应激反应和 DNA 损伤反应的改变。值得注意的是,我们还显示了诱导的神经祖细胞衍生的星形胶质细胞(iNPC-As)在其对神经元的支持能力方面的年龄相关差异,即在促炎刺激下共培养神经元。这些结果表明,iNPC-As 是一种可再生的、易于获得的人类神经胶质细胞资源,保留了供体细胞纤维的与年龄相关的特征,使它们成为一个独特而有价值的模型,可以在人类中枢神经系统健康和疾病中随时间研究人类星形胶质细胞的功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0be/7811849/460067ff15c6/ACEL-20-e13281-g001.jpg

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