Immune Factor, TNFα, Disrupts Human Brain Organoid Development Similar to Schizophrenia—Schizophrenia Increases Developmental Vulnerability to TNFα

Abstract

Schizophrenia (SZ) is a neurodevelopmental genetic disorder in which maternal immune activation (MIA) and increased tumor necrosis factor-α (TNF-α) may contribute. Previous studies using iPSC-derived cerebral organoids and neuronal cells demonstrated developmental malformation and transcriptional dysregulations, including TNF receptors and their signaling genes, common to SZ patients with diverse genetic backgrounds. In the present study, we examined the significance of the common TNF receptor dysregulations by transiently exposing cerebral organoids from embryonic stem cells (ESC) and from representative control and SZ patient iPSCs to TNF. In control iPSC organoids, TNF produced malformations qualitatively similar in, but generally less pronounced than, the malformations of the SZ iPSC-derived organoids. TNF and SZ alone disrupted subcortical rosettes and dispersed proliferating Ki67 + neural progenitor cells (NPC) from the organoid ventricular zone (VZ) into the cortical zone (CZ). In the CZ, the absence of large ramified pan-Neu + neurons coincided with loss of myelinated neurites despite increased cortical accumulation of O4 + oligodendrocytes. The number of calretinin + interneurons increased; however, they lacked the preferential parallel orientation to the organoid surface. SZ and SZ+TNF affected fine cortical and subcortical organoid structure by replacing cells with extracellular matrix (ECM)-like fibers The SZ condition increased developmental vulnerability to TNF,

Loss of Oligodendrocytes by Oxidative Phosphorylation Inhibitor Rotenone and its Reversal by Phenylbutyrate (PB) in Human Brain Developmental Organoid Model

“…The rotenone induced depletion of the Ki67 + cell organoids develop distinct structures: Ventricular zone, intermediate zone, cortical zone, and marginal zone reminiscent of the human brain structures developing in the 1 st and early 2 nd trimesters. As previously shown [38,41], most of the Ki67 + cells were located in rosettes in the ventricular zone, where the proliferating stem/progenitor cells reside. Few of the Ki67 + cells migrated to the intermediate and cortical zones.…”

“…Sections were stained in batches consisting all representative sections from each experimental group and control, as described in Benson, et al [41]. The following primary antibodies were used: Anti-Ki67 polyclonal (rabbit) antibody (Cat #: ab15580, abcam) proliferation marker, and mouse monoclonal anti-O4 antibody IgM at dilution 1:330 (Cat #: MO15002.9, Neuromics), oligodendrocyte Marker.…”

“…The production of organoids in vitro can be used for studies of cell migration, differentiation, basic early neurodevelopment, as well as disease development and progression. The cerebral organoids allowed for the first time to relate the broad Integrative Nuclear FGFR1 Signaling (NFS)linked transcriptional dysregulations found in schizophrenia iPSC neural progenitor cells (NPC) [40] to the development of human brain malformations in schizophrenia and prenatal mother immune attack (MIA) [38,41]. Our laboratory recently showed formation of oligodendrocytes and myelination of cortical neurons in human and their disruptions by genetic factors (schizophrenia) and environmental factor, cytokine TNFα [41].…”

Modeling SARS-CoV-2 infection in individuals with opioid use disorder with brain organoids

“… 89 , 90 Patient-derived organoids confirmed the hypothesized impaired telencephalic neuronal development, attributing it to reduced FGFR1 expression, and also demonstrated aberrant immune response, mitochondrial function, increased TNFα and decreased Wnt signaling, and excitatory/inhibitory neurotransmission. 91 – 95 …”

“…89,90 Patient-derived organoids confirmed the hypothesized impaired telencephalic neuronal development, attributing it to reduced FGFR1 expression, and also demonstrated aberrant immune response, mitochondrial function, increased TNFα and decreased Wnt signaling, and excitatory/inhibitory neurotransmission. [91][92][93][94][95] In addition, mutations in DISC1(disrupted-inschizophrenia 1) have been established as a genetic risk factor for various psychiatric disorders including schizophrenia, but the mechanism of how DISC1 disrupts brain function is not well known. 96,97 Cerebral organoids suggested that disturbing the interaction between DISC1 and Ndel1/Nde1 impairs cell-cycle progression during mitosis.…”