Interferome perturbation of human brain organoids induces progenitor and neuronal dysfunction seen in multiple sclerosis and autism (P2-3.015)

Abstract

<h3>Objective:</h3> To characterize the effect of activation of the interferome in human organoids toward understanding human cortical neuronal dysfunction. <h3>Background:</h3> The mechanisms by which maternal infection and neuroinflammation impact human brain development, function, and repair remain unclear. IFN-g is a proinflammatory cytokine found elevated in serum of pregnant mothers with children diagnosed with autism and in Th1 cells in the cerebrospinal fluid of multiple sclerosis patients. <h3>Design/Methods:</h3> Nearly three hundred human cerebral organoids derived from iPSCs were used across all analyses. Organoids were continually exposed to IFN-g and compared to controls for up to 80 days in culture. 10X single-cell transcriptomics was performed at three timepoints, along with immunolabeling and pulse EdU experiments. Bioinformatic and Markov Chain analyses were used to determine the molecular, cellular, and systems level effects of IFN-g. <h3>Results:</h3> IFN-g exposure at low concentration restricts organoid growth across timepoints, diminishes the pool of cycling radial glia progenitors, and disrupts ventricular adherens cytoarchitecture. We find no evidence of cell cycle arrest or apoptosis, but rather an induction of premature neuronal differentiation and acceleration of neuronal maturation, that stems from cell-type-specific transcriptional rewiring by IFN-g, inducing expression of inflammatory and neurogenic genes that persists in all cell lineages. Markov chain modeling demonstrates that IFN-g targets differentiation lineages in a parallel pan-neuronal fashion. Finally, we find that cell-type-specific gene dysregulation induced by IFN-g overlaps with patient derived organoids from genetically linked autism spectrum disorder, and neuronal intrinsic dysregulation observed in cortical neurons in progressive multiple sclerosis. <h3>Conclusions:</h3> Our results show the feasibility of using a human brain organoid to model the effects of neuroinflammation on human brain development and function. This approach reveals a novel inflammatory mechanistic link with autism and identifies a critical network of neuronal identity and synaptic genes perturbed in multiple sclerosis recapitulated in a preclinical model. <b>Disclosure:</b> Ethan Hollingsworth has nothing to disclose. Mr. Julian has nothing to disclose. Fumihiro Watanabe has nothing to disclose. Mr. Reutershan has nothing to disclose. Miss Julian has nothing to disclose. Ms. Martorell Serra has nothing to disclose. Sofia Lizarraga has nothing to disclose. Dr. Hester has nothing to disclose. Dr. Imitola has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis . The institution of Dr. Imitola has received research support from biogen. Dr. Imitola has a non-compensated relationship as a Board Member with National MS Society that is relevant to AAN interests or activities. Dr. Imitola has a non-compensated relationship as a Committee Member with International Society for Stem Cell Research that is relevant to AAN interests or activities.