TY - JOUR
T1 - A human iPSC-astroglia neurodevelopmental model reveals divergent transcriptomic patterns in schizophrenia
AU - Szabo, Attila
AU - Akkouh, Ibrahim A.
AU - Vandenberghe, Matthieu
AU - Osete, Jordi Requena
AU - Hughes, Timothy
AU - Heine, Vivi
AU - Smeland, Olav B.
AU - Glover, Joel C.
AU - Andreassen, Ole A.
AU - Djurovic, Srdjan
N1 - Funding Information: We thank all participants in this study for their invaluable contribution. In addition, the authors would like to thank Dr. Erlend Strand Gardsjord who was involved in patient recruitment and clinical assessments, research nurses Eivind Bakken and Line Gundersen for obtaining, organizing, and processing skin biopsies, as well as research assistants Lars Hansson, Elin Inderhaug, Evgeniia Frei, and Kristine Kjeldal for their excellent technical assistance in the cultivation of fibroblasts, and with qPCRs. The authors are grateful for the professional assistance of Dr. Zsofia Foldvari (Oslo University Hospital) in creating the artwork of Fig. 1A. We acknowledge the support and use of facilities at the Norwegian Core Facility for Human Pluripotent Stem Cells, under the Norwegian Center for Stem Cell Research, part of the Regional Core Facility network of the Southeastern Regional Health Authority. We thank in particular staff members Hege Brincker Fjerdingstad and Kirstin Buchholz. The sequencing service was provided by the Norwegian Sequencing Centre (www.sequencing.uio.no), a national technology platform hosted by the University of Oslo and supported by the Functional Genomics and Infrastructure programs of the Research Council of Norway and the Southeastern Regional Health Authority. The research leading to these results has received support and funding from Stiftelsen KG Jebsen, from the South-Eastern Norway Regional Health Authority (#2018094) and the Research Council of Norway (#223273). Publisher Copyright: © 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - While neurodevelopmental abnormalities have been associated with schizophrenia (SCZ), the role of astroglia in disease pathophysiology remains poorly understood. In the present study, we used a human induced pluripotent stem cell (iPSC)-derived astrocyte model to investigate the temporal patterns of astroglia differentiation during developmental stages critical for SCZ using RNA sequencing. The model generated astrocyte-specific gene expression patterns during differentiation that corresponded well to astroglia-specific expression signatures of in vivo cortical fetal development. Using this model we identified SCZ-specific expression dynamics, and found that SCZ-associated differentially expressed genes were significantly enriched in the medial prefrontal cortex, striatum, and temporal lobe, targeting VWA5A and ADAMTS19. In addition, SCZ astrocytes displayed alterations in calcium signaling, and significantly decreased glutamate uptake and metalloproteinase activity relative to controls. These results implicate novel transcriptional dynamics in astrocyte differentiation in SCZ together with functional changes that are potentially important biological components of SCZ pathology.
AB - While neurodevelopmental abnormalities have been associated with schizophrenia (SCZ), the role of astroglia in disease pathophysiology remains poorly understood. In the present study, we used a human induced pluripotent stem cell (iPSC)-derived astrocyte model to investigate the temporal patterns of astroglia differentiation during developmental stages critical for SCZ using RNA sequencing. The model generated astrocyte-specific gene expression patterns during differentiation that corresponded well to astroglia-specific expression signatures of in vivo cortical fetal development. Using this model we identified SCZ-specific expression dynamics, and found that SCZ-associated differentially expressed genes were significantly enriched in the medial prefrontal cortex, striatum, and temporal lobe, targeting VWA5A and ADAMTS19. In addition, SCZ astrocytes displayed alterations in calcium signaling, and significantly decreased glutamate uptake and metalloproteinase activity relative to controls. These results implicate novel transcriptional dynamics in astrocyte differentiation in SCZ together with functional changes that are potentially important biological components of SCZ pathology.
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U2 - https://doi.org/10.1038/s41398-021-01681-4
DO - https://doi.org/10.1038/s41398-021-01681-4
M3 - Article
C2 - 34716291
SN - 2158-3188
VL - 11
SP - 1
EP - 13
JO - Translational Psychiatry
JF - Translational Psychiatry
IS - 1
M1 - 554
ER -
