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体外研究人小神经胶质细胞的新兴模型。

Emerging Models to Study Human Microglia In vitro.

机构信息

A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.

Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands.

出版信息

Adv Neurobiol. 2024;37:545-568. doi: 10.1007/978-3-031-55529-9_30.

Abstract

New in vitro models provide an exciting opportunity to study live human microglia. Previously, a major limitation in understanding human microglia in health and disease has been their limited availability. Here, we provide an overview of methods to obtain human stem cell or blood monocyte-derived microglia-like cells that provide a nearly unlimited source of live human microglia for research. We address how understanding microglial ontogeny can help modeling microglial identity and function in a dish with increased accuracy. Moreover, we categorize stem cell-derived differentiation methods into embryoid body based, growth factor driven, and coculture-driven approaches, and review novel viral approaches to reprogram stem cells directly into microglia-like cells. Furthermore, we review typical readouts used in the field to verify microglial identity and characterize functional microglial phenotypes. We provide an overview of methods used to study microglia in environments more closely resembling the (developing) human CNS, such as cocultures and brain organoid systems with incorporated or innately developing microglia. We highlight how microglia-like cells can be utilized to reveal molecular and functional mechanisms in human disease context, focusing on Alzheimer's disease and other neurodegenerative diseases as well as neurodevelopmental diseases. Finally, we provide a critical overview of challenges and future opportunities to more accurately model human microglia in a dish and conclude that novel in vitro microglia-like cells provide an exciting potential to bring preclinical research of microglia to a new era.

摘要

新型体外模型为研究活体人类小胶质细胞提供了一个令人兴奋的机会。此前,了解健康和疾病中的人类小胶质细胞的主要限制因素是它们的可用性有限。在这里,我们提供了一种概述,介绍了获得人类干细胞或血液单核细胞衍生的小胶质样细胞的方法,这些方法为研究提供了几乎无限的活体人类小胶质细胞来源。我们探讨了理解小胶质细胞发生如何有助于更准确地在培养皿中模拟小胶质细胞的身份和功能。此外,我们将基于胚胎体的、生长因子驱动的和共培养驱动的分化方法进行分类,并回顾了将干细胞直接重编程为小胶质样细胞的新型病毒方法。此外,我们还回顾了该领域中用于验证小胶质细胞身份和表征功能性小胶质细胞表型的典型检测方法。我们概述了用于研究更接近(发育中的)人类中枢神经系统环境中小胶质细胞的方法,例如共培养和脑类器官系统,其中包含或固有地发育有小胶质细胞。我们强调了小胶质样细胞如何用于揭示人类疾病背景下的分子和功能机制,重点关注阿尔茨海默病和其他神经退行性疾病以及神经发育性疾病。最后,我们对更准确地在培养皿中模拟人类小胶质细胞的挑战和未来机遇进行了批判性概述,并得出结论,新型体外小胶质样细胞为将小胶质细胞的临床前研究带入一个新时代提供了令人兴奋的潜力。

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