Klotho抑制人脑类器官的神经元衰老。

IF 5.4 Q1 GERIATRICS & GERONTOLOGY NPJ Aging and Mechanisms of Disease Pub Date : 2021-08-02 DOI:10.1038/s41514-021-00070-x
Mohammed R Shaker, Julio Aguado, Harman Kaur Chaggar, Ernst J Wolvetang
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引用次数: 14

摘要

衰老是许多神经退行性疾病的主要危险因素。Klotho (KL)是一种糖基化的跨膜蛋白,在脑脉络膜丛和神经元中表达。KL对体内多种细胞类型具有有效的抗衰老作用,但其在人类脑细胞中的作用仍不清楚。本研究表明,来源于2D培养的人类多能干细胞或皮质类器官的人类皮质神经元,在体外长时间维持时,会发展出衰老细胞的典型特征,并且皮质类器官中内源性KL表达的适度上调或抑制分别抑制和加速衰老。我们进一步证明,KL的表达改变了衰老相关基因的表达,包括细胞外基质基因和蛋白多糖,并能以旁分泌方式抑制神经元衰老。综上所述,我们的研究结果确立了KL在调节人类神经元衰老中的重要作用,并为其在人类大脑衰老中的作用提供了新的机制见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Klotho inhibits neuronal senescence in human brain organoids.

Aging is a major risk factor for many neurodegenerative diseases. Klotho (KL) is a glycosylated transmembrane protein that is expressed in the choroid plexus and neurons of the brain. KL exerts potent anti-aging effects on multiple cell types in the body but its role in human brain cells remains largely unclear. Here we show that human cortical neurons, derived from human pluripotent stem cells in 2D cultures or in cortical organoids, develop the typical hallmarks of senescent cells when maintained in vitro for prolonged periods of time, and that moderate upregulation or repression of endogenous KL expression in cortical organoids inhibits and accelerates senescence, respectively. We further demonstrate that KL expression alters the expression of senescence-associated genes including, extracellular matrix genes, and proteoglycans, and can act in a paracrine fashion to inhibit neuronal senescence. In summary, our results establish an important role for KL in the regulation of human neuronal senescence and offer new mechanistic insight into its role in human brain aging.

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来源期刊
NPJ Aging and Mechanisms of Disease
NPJ Aging and Mechanisms of Disease Medicine-Geriatrics and Gerontology
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8 weeks
期刊介绍: npj Aging and Mechanisms of Disease is an online open access journal that provides a forum for the world’s most important research in the fields of aging and aging-related disease. The journal publishes papers from all relevant disciplines, encouraging those that shed light on the mechanisms behind aging and the associated diseases. The journal’s scope includes, but is not restricted to, the following areas (not listed in order of preference): • cellular and molecular mechanisms of aging and aging-related diseases • interventions to affect the process of aging and longevity • homeostatic regulation and aging • age-associated complications • translational research into prevention and treatment of aging-related diseases • mechanistic bases for epidemiological aspects of aging-related disease.
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