A characterization of the molecular phenotype and inflammatory response of schizophrenia patient-derived microglia-like cells

Ormel, Paul R.; Böttcher, Chotima; Gigase, Frederieke; Missall, Roy; Zuiden, Welmoed van; Zapata, M Camila Fernández; Ilhan, Dilara; Goeij, Michelle de; Udine, Evan; Sommer, Iris; Priller, Josef; Raj, Towfique; Kahn, René S.; Hol, Elly M.; Witte, Lot de

doi:10.1016/j.bbi.2020.08.012

Cited by 39 publications

(41 citation statements)

References 46 publications

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“…Sellgren et al demonstrated that iMG cells would be a good model to study schizophrenia. Several other groups have successfully applied this iMG model or similar model to study the microglial functions in different disorders, including bipolar disorder, fibromyalgia, and schizophrenia (Ohgidani et al, 2017a,b;Ormel et al, 2020). In this study, we demonstrated that the iMG cellular model would also be a good model for studying cellular changes and gene regulation during the development of AD, mainly the phagocytosis of fAβ 42 and the gene expression profiles.…”

Section: Discussionmentioning

confidence: 53%

Validation of Induced Microglia-Like Cells (iMG Cells) for Future Studies of Brain Diseases

Banerjee

et al. 2021

Front. Cell. Neurosci.

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Microglia are the primary resident immune cells of the central nervous system that maintain physiological homeostasis in the brain and contribute to the pathogenesis of many psychiatric disorders and neurodegenerative diseases. Due to the lack of appropriate human cellular models, it is difficult to study the basic pathophysiological processes linking microglia to brain diseases. In this study, we adopted a microglia-like cellular model derived from peripheral blood monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-34 (IL-34). We characterized and validated this in vitro cellular model by morphology, immunocytochemistry, gene expression profiles, and functional study. Our results indicated that the iMG cells developed typical microglial ramified morphology, expressed microglial specific surface markers (P2RY12 and TMEM119), and possessed phagocytic activity. Principal component analyses and multidimensional scaling analyses of RNA-seq data showed that iMG cells were distinct from monocytes and induced macrophages (iMacs) but clustered closer to human microglia and hiPSC-induced microglia. Heatmap analyses also found that iMG cells, but not monocytes, were closely clustered with human primary microglia. Further pathway and relative expression analysis indicated that unique genes from iMG cells were involved in the regulation of the complement system, especially in the synapse and ion transport. Overall, our data demonstrated that the iMG model mimicked many features of the brain resident microglia, highlighting its utility in the study of microglial function in many brain diseases, such as schizophrenia and Alzheimer's disease (AD).

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Section: Discussionmentioning

confidence: 53%

Validation of Induced Microglia-Like Cells (iMG Cells) for Future Studies of Brain Diseases

Banerjee

et al. 2021

Front. Cell. Neurosci.

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“…In an effort to develop more representative in vitro models of human microglia, we used MDMi, a model system of microglia-like cells that has emerged as a promising, patient-specific drug screening platform for neurological diseases ( 55, 56 ). Previous reports have shown that MDMi morphologically and functionally resemble brain-resident human microglia and express bonafide microglial markers ( 28–31 ). In this study, we developed novel MDMi platforms that incorporate relevant in vivo cues resembling the microenvironment of the brain.…”

Section: Discussionmentioning

confidence: 96%

“…The monocyte-derived microglia-like cell (MDMi) model system addresses the shortcoming of the above models and provides a novel, cost-effective approach for the rapid generation of personalised microglia cultures from living patients. This method has been previously applied by us and others using ex vivo blood-derived monocytes from schizophrenia ( 27, 28 ), Nasu-Hakola disease ( 29 ) and amyotrophic lateral sclerosis (ALS) ( 30 ) patients, demonstrating disease-associated phenotypes in the patient-derived MDMi. In addition to their controlled genetic background, MDMi are readily available and yield mature microglia in a short time frame, thus allowing for the study of mature microglia from large patient cohorts ( 31, 32 ).…”

Section: Introductionmentioning

confidence: 99%

3D models of Alzheimer’s disease patient microglia recapitulate disease phenotype and show differential drug responses compared to 2D

Cuní-López

Quek

Oikari

et al. 2021

Preprint

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Alzheimer’s disease (AD) is an incurable neurodegenerative disorder with a rapidly increasing prevalence worldwide. Current approaches targeting hallmark pathological features of AD have had no consistent clinical benefit. Neuroinflammation is a major contributor to neurodegeneration and hence, microglia, the brain’s resident immune cells, are an attractive target for potentially more effective therapeutic strategies. However, there is no current in vitro model system that faithfully recapitulates patient-specific microglial characteristics. To address this shortcoming, we developed novel 3D models of monocyte-derived microglia-like cells (MDMi) from AD patients. MDMi in 3D exhibited mature microglial features, including a highly branched morphology and enhanced bonafide microglial marker expression compared to 2D. Moreover, AD MDMi in 3D co-cultures with neuro-glial cells showed altered cell-to-cell interactions, growth factor and cytokine secretion profiles and responses to amyloid-β. Drug screening assays in 3D AD MDMi revealed different cytokine responses compared to 2D. Our study demonstrates disease- and drug-specific responses in 3D MDMi models that are not apparent in 2D and presents a new 3D platform for more effective and personalised drug testing.

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“…Complementary experiments on HEK293 cells transfected with Ala55Thr-expressing vector demonstrated a reduction in Akt phosphorylation-mediated signaling upon CX3CL1 treatment [ 159 ]. A characterization of microglia-like cells derived from patients with schizophrenia demonstrated the presence of two unique inflammatory phenotypes within these cells [ 160 ]. It is noteworthy that one out of the significantly abundant clusters was distinguished by higher expression of CX3CR1 .…”

Section: The Implication Of the Cx3cl1–cx3cr1 Signaling Pathway In Schizophreniamentioning

confidence: 99%

Shedding light on the role of CX3CR1 in the pathogenesis of schizophrenia

2021

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Schizophrenia has a complex and heterogeneous molecular and clinical picture. Over the years of research on this disease, many factors have been suggested to contribute to its pathogenesis. Recently, the inflammatory processes have gained particular interest in the context of schizophrenia due to the increasing evidence from epidemiological, clinical and experimental studies. Within the immunological component, special attention has been brought to chemokines and their receptors. Among them, CX3C chemokine receptor 1 (CX3CR1), which belongs to the family of seven-transmembrane G protein-coupled receptors, and its cognate ligand (CX3CL1) constitute a unique system in the central nervous system. In the view of regulation of the brain homeostasis through immune response, as well as control of microglia reactivity, the CX3CL1–CX3CR1 system may represent an attractive target for further research and schizophrenia treatment. In the review, we described the general characteristics of the CX3CL1–CX3CR1 axis and the involvement of this signaling pathway in the physiological processes whose disruptions are reported to participate in mechanisms underlying schizophrenia. Furthermore, based on the available clinical and experimental data, we presented a guide to understanding the implication of the CX3CL1–CX3CR1 dysfunctions in the course of schizophrenia.

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A characterization of the molecular phenotype and inflammatory response of schizophrenia patient-derived microglia-like cells

Abstract: 2020). A characterization of the molecular phenotype and inflammatory response of schizophrenia patient-derived microglia-like cells. Brain behavior and immunity, 90, 196-207.

Cited by 39 publications

References 46 publications

Validation of Induced Microglia-Like Cells (iMG Cells) for Future Studies of Brain Diseases

Validation of Induced Microglia-Like Cells (iMG Cells) for Future Studies of Brain Diseases

3D models of Alzheimer’s disease patient microglia recapitulate disease phenotype and show differential drug responses compared to 2D

Shedding light on the role of CX3CR1 in the pathogenesis of schizophrenia

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