Heider Johanna, Vogel Sabrina, Volkmer Hansjürgen, Breitmeyer Ricarda
Molecular Neurobiology, NMI Natural and Medical Sciences Institute at the University of Tübingen, 72770 Reutlingen, Germany.
Int J Mol Sci. 2021 Sep 23;22(19):10254. doi: 10.3390/ijms221910254.
Neuropsychiatric disorders such as schizophrenia or autism spectrum disorder represent a leading and growing burden on worldwide mental health. Fundamental lack in understanding the underlying pathobiology compromises efficient drug development despite the immense medical need. So far, antipsychotic drugs reduce symptom severity and enhance quality of life, but there is no cure available. On the molecular level, schizophrenia and autism spectrum disorders correlate with compromised neuronal phenotypes. There is increasing evidence that aberrant neuroinflammatory responses of glial cells account for synaptic pathologies through deregulated communication and reciprocal modulation. Consequently, microglia and astrocytes emerge as central targets for anti-inflammatory treatment to preserve organization and homeostasis of the central nervous system. Studying the impact of neuroinflammation in the context of neuropsychiatric disorders is, however, limited by the lack of relevant human cellular test systems that are able to represent the dynamic cellular processes and molecular changes observed in human tissue. Today, patient-derived induced pluripotent stem cells offer the opportunity to study neuroinflammatory mechanisms in vitro that comprise the genetic background of affected patients. In this review, we summarize the major findings of iPSC-based microglia and astrocyte research in the context of neuropsychiatric diseases and highlight the benefit of 2D and 3D co-culture models for the generation of efficient in vitro models for target screening and drug development.
精神分裂症或自闭症谱系障碍等神经精神疾病给全球心理健康带来了日益严重的主要负担。尽管存在巨大的医疗需求，但对潜在病理生物学的根本缺乏了解阻碍了高效的药物开发。到目前为止，抗精神病药物可减轻症状严重程度并提高生活质量，但尚无治愈方法。在分子水平上，精神分裂症和自闭症谱系障碍与神经元表型受损相关。越来越多的证据表明，胶质细胞异常的神经炎症反应通过失调的通讯和相互调节导致突触病变。因此，小胶质细胞和星形胶质细胞成为抗炎治疗的核心靶点，以维持中枢神经系统的组织和稳态。然而，由于缺乏能够代表在人体组织中观察到的动态细胞过程和分子变化的相关人类细胞测试系统，在神经精神疾病背景下研究神经炎症的影响受到限制。如今，患者来源的诱导多能干细胞为在体外研究包括受影响患者遗传背景的神经炎症机制提供了机会。在这篇综述中，我们总结了在神经精神疾病背景下基于诱导多能干细胞的小胶质细胞和星形胶质细胞研究的主要发现，并强调了二维和三维共培养模型在生成用于靶点筛选和药物开发的高效体外模型方面的益处。
