Neuroimmune cortical organoids overexpressing C4A exhibit multiple schizophrenia endophenotypes

Abstract

Elevated expression of the complement component 4A (C4A) protein has been linked to an increased risk of schizophrenia (SCZ). However, there are few human models available to study the mechanisms by which C4A contributes to the development of SCZ. In this study, we established a C4A overexpressing neuroimmune cortical organoid (NICO) model, which includes mature neuronal cells, astrocytes, and functional microglia. The C4A NICO model recapitulated several neuroimmune endophenotypes observed in SCZ patients, including modulation of inflammatory genes and increased cytokine secretion. C4A expression also increased microglia-mediated synaptic uptake in the NICO model, supporting the hypothesis that synapse and brain volume loss in SCZ patients may be due to excessive microglial pruning. Our results highlight the role of C4A in the immunogenetic risk factors for SCZ and provide a human model for phenotypic discovery and validation of immunomodulating therapies.

Cell specificity of adeno-associated virus (AAV) serotypes in human cortical organoids

“…Induced pluripotent stem cell (iPSC) derived hCOs represent a promising complex in vitro human model class to study AAV gene therapies as they contain organized three-dimensional tissue architecture and a diversity of CNS cell types, including excitatory neurons, inhibitory neurons, astrocytes, and choroid plexus cells [14][15][16] . Organoid cell diversity and self-organized tissue structure yield a physiologically realistic system that has been used to model various neurological disease phenotypes including Alzheimer's, frontotemporal dementia, and schizophrenia [17][18][19] . hCOs can serve as a useful non-animal model to examine AAVs and provide human physiological insight into AAV transduction efficiency, toxicity, and cell tropism in the CNS 20 .…”