TY - JOUR
T1 - Attenuated transcriptional response to pro-inflammatory cytokines in schizophrenia hiPSC-derived neural progenitor cells
AU - Bhat, Anjali
AU - Irizar, Haritz
AU - Couch, Amalie
AU - Raval, Pooja
AU - Duarte, Rodrigo R R
AU - Dutan Polit, Lucia
AU - Hanger, Bjorn
AU - Powell, Timothy
AU - Michael Deans, P J
AU - Shum, Carol
AU - Nagy, Roland
AU - McAlonan, Grainne
AU - Iyegbe, Conrad O
AU - Price, Jack
AU - Bramon, Elvira
AU - Bhattacharyya, Sagnik
AU - Vernon, Anthony C
AU - Srivastava, Deepak P
N1 - Funding Information:
We would like to thank all of the participants who took part in this research, as well as the clinical staff who facilitated their involvement. The work (at King’s College, London) was also supported by the Medical Research Council (MRC) Centre grant (MR/N026063/1). A.B. was supported by a Medical Research Council doctoral studentship [MR/N013867/1] for this work. H.I. received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 747429. The study was supported by grants from StemBANCC: the Innovative Medicines Initiative joint undertaking under grant 115439-2, whose resources are composed of financial contribution from the European Union [FP7/2007-2013] and EFPIA companies’ in-kind contribution (JP, DPS); MATRICS: the European Union's Seventh Framework Programme (FP7-HEALTH-603016) (DPS, JP). In addition, funds from the Wellcome Trust ISSF Grant (No. 097819) and the King's Health Partners Research and Development Challenge Fund, a fund administered on behalf of King's Health Partners by Guy's and St Thomas’ Charity awarded to DPS; the Brain and Behavior Foundation (formally National Alliance for Research on Schizophrenia and Depression (NARSAD); Grant No. 25957), awarded to DPS. A.C. is supported by a NC3Rs studentship (NC/S001506/1) awarded to A.C.V and D.P.S. The work at King’s College London was also supported by an Medical Research Council Centre Grant (MR/N026063/1). E.B. thanks the following funders: the National Institute for Health Research (NIHR200756); Mental Health Research UK John Grace QC Scholarship 2018; BMA Margaret Temple Fellowships 2016 and 2006; Medical Research Council (MRC) and Korean Health Industry Development Institute Partnering Award (MC_PC_16014); MRC New Investigator Award (G0901310); MRC Centenary Award (G1100583); MRC project grant G1100583; a National Institute for Health Research UK post-doctoral fellowship (PDA/02/06/016); the Psychiatry Research Trust; the Schizophrenia Research Fund; the Brain and Behaviour Research Foundation’s NARSAD Young Investigator Awards 2005 and 2008; a Wellcome Trust Research Training Fellowship; Wellcome Trust Case Control Consortium awards (085475/B/08/Z and 085475/Z/08/Z); and the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry King’s College London. SB has been supported by a National Institute for Health Research (NIHR) Clinician Scientist Award (NIHR CS-11-001) and grants from the Medical Research Council (MR/J012149/1) and NIHR Efficacy and Mechanism Evaluation scheme (16/126/53). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. In addition, this paper represents independent research part funded by the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The authors thank the Wohl Cellular Imaging Centre (WCIC) at the IoPPN, King's College, London, for help with microscopy.
Funding Information:
We would like to thank all of the participants who took part in this research, as well as the clinical staff who facilitated their involvement. The work (at King's College, London) was also supported by the Medical Research Council (MRC) Centre grant (MR/N026063/1). A.B. was supported by a Medical Research Council doctoral studentship [MR/N013867/1] for this work. H.I. received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 747429. The study was supported by grants from StemBANCC: the Innovative Medicines Initiative joint undertaking under grant 115439-2, whose resources are composed of financial contribution from the European Union [FP7/2007-2013] and EFPIA companies’ in-kind contribution (JP, DPS); MATRICS: the European Union's Seventh Framework Programme (FP7-HEALTH-603016) (DPS, JP). In addition, funds from the Wellcome Trust ISSF Grant (No. 097819) and the King's Health Partners Research and Development Challenge Fund, a fund administered on behalf of King's Health Partners by Guy's and St Thomas’ Charity awarded to DPS; the Brain and Behavior Foundation (formally National Alliance for Research on Schizophrenia and Depression (NARSAD); Grant No. 25957), awarded to DPS. A.C. is supported by a NC3Rs studentship (NC/S001506/1) awarded to A.C.V and D.P.S. The work at King's College London was also supported by an Medical Research Council Centre Grant (MR/N026063/1). E.B. thanks the following funders: the National Institute for Health Research (NIHR200756); Mental Health Research UK John Grace QC Scholarship 2018; BMA Margaret Temple Fellowships 2016 and 2006; Medical Research Council (MRC) and Korean Health Industry Development Institute Partnering Award (MC_PC_16014); MRC New Investigator Award (G0901310); MRC Centenary Award (G1100583); MRC project grant G1100583; a National Institute for Health Research UK post-doctoral fellowship (PDA/02/06/016); the Psychiatry Research Trust; the Schizophrenia Research Fund; the Brain and Behaviour Research Foundation's NARSAD Young Investigator Awards 2005 and 2008; a Wellcome Trust Research Training Fellowship; Wellcome Trust Case Control Consortium awards (085475/B/08/Z and 085475/Z/08/Z); and the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry King's College London. SB has been supported by a National Institute for Health Research (NIHR) Clinician Scientist Award (NIHR CS-11-001) and grants from the Medical Research Council (MR/J012149/1) and NIHR Efficacy and Mechanism Evaluation scheme (16/126/53). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. In addition, this paper represents independent research part funded by the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The authors thank the Wohl Cellular Imaging Centre (WCIC) at the IoPPN, King's College, London, for help with microscopy. RNA sequencing data reported in this paper is available at https://www.ncbi.nlm.nih.gov/subs/sra/SUB10767669. Previously unpublished code used for statistical analyses reported in this paper is available on GitHub: github.com/abhat92/DGE_response_to_cytokines_in_SZ_hiPSC-NPCs.
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/10
Y1 - 2022/10
N2 - Maternal immune activation (MIA) during prenatal development is an environmental risk factor for psychiatric disorders including schizophrenia (SZ). Converging lines of evidence from human and animal model studies suggest that elevated cytokine levels in the maternal and fetal compartments are an important indication of the mechanisms driving this association. However, there is variability in susceptibility to the psychiatric risk conferred by MIA, likely influenced by genetic factors. How MIA interacts with a genetic profile susceptible to SZ is challenging to test in animal models. To address this gap, we examined whether differential gene expression responses occur in forebrain-lineage neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSC) generated from three individuals with a diagnosis of schizophrenia and three healthy controls. Following acute (24 h) treatment with either interferon-gamma (IFNγ; 25 ng/μl) or interleukin (IL)-1β (10 ng/μl), we identified, by RNA sequencing, 3380 differentially expressed genes (DEGs) in the IFNγ-treated control lines (compared to untreated controls), and 1980 DEGs in IFNγ-treated SZ lines (compared to untreated SZ lines). Out of 4137 genes that responded significantly to IFNγ across all lines, 1223 were common to both SZ and control lines. The 2914 genes that appeared to respond differentially to IFNγ treatment in SZ lines were subjected to a further test of significance (multiple testing correction applied to the interaction effect between IFNγ treatment and SZ diagnosis), yielding 359 genes that passed the significance threshold. There were no differentially expressed genes in the IL-1β-treatment conditions after Benjamini-Hochberg correction. Gene set enrichment analysis however showed that IL-1β impacts immune function and neuronal differentiation. Overall, our data suggest that a) SZ NPCs show an attenuated transcriptional response to IFNγ treatment compared to controls; b) Due to low IL-1β receptor expression in NPCs, NPC cultures appear to be less responsive to IL-1β than IFNγ; and c) the genes differentially regulated in SZ lines – in the face of a cytokine challenge – are primarily associated with mitochondrial, “loss-of-function”, pre- and post-synaptic gene sets. Our findings particularly highlight the role of early synaptic development in the association between maternal immune activation and schizophrenia risk.
AB - Maternal immune activation (MIA) during prenatal development is an environmental risk factor for psychiatric disorders including schizophrenia (SZ). Converging lines of evidence from human and animal model studies suggest that elevated cytokine levels in the maternal and fetal compartments are an important indication of the mechanisms driving this association. However, there is variability in susceptibility to the psychiatric risk conferred by MIA, likely influenced by genetic factors. How MIA interacts with a genetic profile susceptible to SZ is challenging to test in animal models. To address this gap, we examined whether differential gene expression responses occur in forebrain-lineage neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSC) generated from three individuals with a diagnosis of schizophrenia and three healthy controls. Following acute (24 h) treatment with either interferon-gamma (IFNγ; 25 ng/μl) or interleukin (IL)-1β (10 ng/μl), we identified, by RNA sequencing, 3380 differentially expressed genes (DEGs) in the IFNγ-treated control lines (compared to untreated controls), and 1980 DEGs in IFNγ-treated SZ lines (compared to untreated SZ lines). Out of 4137 genes that responded significantly to IFNγ across all lines, 1223 were common to both SZ and control lines. The 2914 genes that appeared to respond differentially to IFNγ treatment in SZ lines were subjected to a further test of significance (multiple testing correction applied to the interaction effect between IFNγ treatment and SZ diagnosis), yielding 359 genes that passed the significance threshold. There were no differentially expressed genes in the IL-1β-treatment conditions after Benjamini-Hochberg correction. Gene set enrichment analysis however showed that IL-1β impacts immune function and neuronal differentiation. Overall, our data suggest that a) SZ NPCs show an attenuated transcriptional response to IFNγ treatment compared to controls; b) Due to low IL-1β receptor expression in NPCs, NPC cultures appear to be less responsive to IL-1β than IFNγ; and c) the genes differentially regulated in SZ lines – in the face of a cytokine challenge – are primarily associated with mitochondrial, “loss-of-function”, pre- and post-synaptic gene sets. Our findings particularly highlight the role of early synaptic development in the association between maternal immune activation and schizophrenia risk.
UR - http://www.scopus.com/inward/record.url?scp=85133903015&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2022.06.010
DO - 10.1016/j.bbi.2022.06.010
M3 - Article
C2 - 35716830
SN - 0889-1591
VL - 105
SP - 82
EP - 97
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -