Abstract
BackgroundReprogramming human induced pluripotent stem cells (iPSCs) from somatic cells and generating three-dimensional brain organoids from these iPSCs provide access to live human neuronal tissue with disease-specific genetic backgrounds.MethodsCerebral organoids were generated from iPSCs of eight bipolar disorder (BPI) patients and eight healthy control individuals. RNA-seq experiments were undertaken using RNA isolated from the cerebral organoids. Functional activity in the cerebral organoids was studied using microelectrode arrays.ResultsRNA-seq data comparing gene expression profiles in the cerebral organoids showed downregulation of pathways involved in cell adhesion, neurodevelopment, and synaptic biology in bipolar disorder along with upregulation of genes involved in immune signaling. The central hub in the network analysis was neurocan (NCAN), which is located in a locus with evidence for genome-wide significant association in BPI. Gene ontology analyses suggested deficits related to endoplasmic reticulum biology in BPI, which was supported by cellular characterization of ER–mitochondria interactions. Functional studies with microelectrode arrays revealed specific deficits in response to stimulation and depolarization in BPI cerebral organoids.ConclusionsOur studies in cerebral organoids from bipolar disorder showed dysregulation in genes involved in cell adhesion, immune signaling, and endoplasmic reticulum biology; implicated a central role for the GWAS hit NCAN in the biology of BPI; and showed evidence of deficits in neurotransmission.
Highlights
Reprogramming human induced pluripotent stem cells from somatic cells and generating three-dimensional brain organoids from these iPSCs provide access to live human neuronal tissue with diseasespecific genetic backgrounds
Generation and characterization of cerebral organoids The iPSCs reprogrammed from fibroblasts of patients with bipolar disorder (BPI) and healthy control individuals were differentiated along the telencephalic lineage to generate cerebral organoids [18]
There were no gross differences between cerebral organoids generated from BPI iPSCs compared to those generated from control iPSCs
Summary
Reprogramming human induced pluripotent stem cells (iPSCs) from somatic cells and generating three-dimensional brain organoids from these iPSCs provide access to live human neuronal tissue with diseasespecific genetic backgrounds. IPSCs can be differentiated along the neuronal lineage to generate a range of neuronal cell types and tissue that have disease-specific genetic backgrounds [10, 11]. These approaches are being applied to investigations of the disease biology of psychiatric disorders, including BPI [12,13,14,15]. Cerebral organoids from human iPSCs recapitulate human cortical development and contain many neuronal and glial subtypes found in the human brain, including mature cortical neuron subtypes and synapses as well as networks of connectivity between different cells in the self-organizing structures [18,19,20]
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