Hanger Bjørn, Couch Amalie, Rajendran Lawrence, Srivastava Deepak P, Vernon Anthony C
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, United Kingdom.
UK Dementia Research Institute, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.
Front Psychiatry. 2020 Aug 11;11:789. doi: 10.3389/fpsyt.2020.00789. eCollection 2020.
Microglia, the resident tissue macrophages of the brain, are increasingly implicated in the pathophysiology of psychiatric disorders with a neurodevelopmental origin, including schizophrenia. To date, however, our understanding of the potential role for these cells in schizophrenia has been informed by studies of aged samples, low resolution neuroimaging and rodent models. Whilst these have provided important insights, including signs of the heterogeneous nature of microglia, we currently lack a validated human system to characterize microglia in the context of brain health and disease during neurodevelopment. Primarily, this reflects a lack of access to human primary tissue during developmental stages. In this review, we first describe microglia, including their ontogeny and heterogeneity and consider their role in brain development. We then provide an evaluation of the potential for differentiating microglia from human induced pluripotent stem cells (hiPSCs) as a robust human model system to study these cells. We find the majority of protocols for hiPSC-derived microglia generate cells characteristically similar to foetal stage microglia when exposed to neuronal environment-like cues. This may represent a robust and relevant model for the study of cellular and molecular mechanisms in schizophrenia. Each protocol however, provides unique benefits as well as shortcomings, highlighting the need for context-dependent protocol choice and cross-lab collaboration and communication to identify the most robust and translatable microglia model.
小胶质细胞是大脑中的常驻组织巨噬细胞，越来越多地被认为与包括精神分裂症在内的具有神经发育起源的精神疾病的病理生理学有关。然而，迄今为止，我们对这些细胞在精神分裂症中潜在作用的理解是基于对老年样本、低分辨率神经影像学和啮齿动物模型的研究。虽然这些研究提供了重要的见解，包括小胶质细胞异质性的迹象，但我们目前缺乏一个经过验证的人类系统来在神经发育过程中的脑健康和疾病背景下对小胶质细胞进行表征。主要原因是在发育阶段难以获取人类原代组织。在这篇综述中，我们首先描述小胶质细胞，包括它们的个体发生和异质性，并探讨它们在大脑发育中的作用。然后，我们评估了将小胶质细胞从人类诱导多能干细胞（hiPSC）中分化出来作为研究这些细胞的强大人类模型系统的潜力。我们发现，当暴露于类似神经元环境的线索时，大多数用于hiPSC衍生小胶质细胞的方案所产生的细胞在特征上与胎儿期小胶质细胞相似。这可能代表了一个用于研究精神分裂症细胞和分子机制的强大且相关的模型。然而，每个方案都有独特的优点和缺点，这突出了根据具体情况选择方案以及跨实验室合作与交流以确定最强大且可转化的小胶质细胞模型的必要性。
