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Updated: Dec 11, 2025
Author Spotlight: Induced Microglia-Like Cell Technology to Shed Light on the Role of Microglial Dysfunction in Neuropsychiatric Disorders
Published on: September 6, 2024
A characterization of the molecular phenotype and inflammatory response of schizophrenia patient-derived
Paul R Ormel1, Chotima Böttcher2, Frederieke A J Gigase3
1Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands; Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
Abstract:
Different lines of evidence support a causal role for microglia in the pathogenesis of schizophrenia. However, how schizophrenia patient-derived microglia are affected at the phenotypic and functional level is still largely unknown. We used a recently described model to induce patient-derived microglia-like cells and used this to analyze changes in the molecular phenotype and function of myeloid cells in schizophrenia. We isolated monocytes from twenty recent-onset schizophrenia patients and twenty non-psychiatric controls. We cultured the cells towards an induced microglia-like phenotype (iMG), analyzed the phenotype of the cells by RNA sequencing and mass cytometry, and their response to LPS. Mass cytometry showed a high heterogeneity of iMG in cells derived from patients as well as controls. The prevalence of two iMG clusters was significantly higher in schizophrenia patients (adjusted p-value < 0.001). These subsets are characterized by expression of ApoE, Ccr2, CD18, CD44, and CD95, as well as IRF8, P2Y12, Cx3cr1 and HLA-DR. In addition, we found that patient-derived iMG show an enhanced response to LPS, with increased secretion of TNF-α. Further studies are needed to replicate these findings, to determine whether similar subclusters are present in schizophrenia patients in vivo, and to address how these subclusters are related to the increased response to LPS, as well as other microglial functions.
Insights
Schizophrenia patients exhibit distinct microglia-like cell subsets with heightened inflammatory responses. These findings highlight potential new therapeutic targets for schizophrenia by understanding myeloid cell alterations.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia are implicated in schizophrenia pathogenesis, but their specific alterations in patients remain unclear.
- Understanding patient-derived myeloid cell phenotypes is crucial for elucidating schizophrenia's biological mechanisms.
Purpose of the Study:
- To investigate the molecular phenotype and function of induced microglia-like cells (iMG) derived from schizophrenia patients.
- To identify specific myeloid cell subsets and their functional changes associated with schizophrenia.
Main Methods:
- Monocytes were isolated from 20 schizophrenia patients and 20 controls, then differentiated into iMG.
- RNA sequencing and mass cytometry were employed to analyze iMG phenotype and heterogeneity.
- LPS stimulation assessed iMG functional responses, including cytokine secretion.
Main Results:
- Induced microglia-like cells displayed significant heterogeneity in both patient and control groups.
- Two specific iMG clusters were found at significantly higher prevalence in schizophrenia patients.
- Patient-derived iMG showed an enhanced pro-inflammatory response to LPS, indicated by increased TNF-α secretion.
Conclusions:
- Schizophrenia is associated with distinct, potentially pro-inflammatory, myeloid cell subsets.
- These findings suggest that altered microglia phenotypes contribute to schizophrenia pathophysiology.
- Further in vivo studies are required to validate these patient-derived cell findings and explore therapeutic implications.
