Human iPSC-Derived Glia as a Tool for Neuropsychiatric Research and Drug Development

Abstract

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.

Microglia sequelae: brain signature of innate immunity in schizophrenia

“…The limitations associated to neuroimaging data highlights the need of more adequate tools to evaluate schizophrenia-associated microglia sequelae, that may include data from human iPSC-derived glia (as reviewed in refs. [133,134]).…”

The Janus face of antipsychotics in glial cells: Focus on glioprotection

“…20,21 In terms of astrocytes and dopamine-glutamate neurotransmitter systems, D2 receptors are highly expressed in astrocytes 22,23 and, therefore, glial cells may participate in the pathophysiology of neuropsychiatric disorders, and may consequently be involved in the mechanism of action of antipsychotic drugs. 24,25 Excessive activation of dopamine receptors can lead to a decrease in the activity of the glutamatergic system, which contributes to psychotic symptoms, commonly observed in neuropsychiatric disorders. By blocking dopamine receptors, antipsychotics can increase the activity of the glutamatergic system, helping to reduce psychotic symptoms.…”

“…20,21 In terms of astrocytes and dopamine-glutamate neurotransmitter systems, D2 receptors are highly expressed in astrocytes 22,23 and, therefore, glial cells may participate in the pathophysiology of neuropsychiatric disorders, and may consequently be involved in the mechanism of action of antipsychotic drugs. 24,25…”

Induced pluripotent stem cell‐based assays recapture multiple properties of human astrocytes

“…After the advent of induced pluripotent stem cells (iPSCs), besides rodent models, astrocytes derived from patient iPSCs have been a research resource for human astrocyte diseases. Protocols of astrocyte differentiation from human iPSCs have been reported 2–8 . Although we previously reported a differentiation method for astrocytes as well as a disease modelling capability protocol, 9 methods for the induction and analysis of multiple properties of human astrocytes have yet to be established.…”