Maternal immune activation: advancing from rodents to humans through a development of a hIPSC model to study gene x environment interactions

Human induced pluripotent stem cells (hIPSCs) present a unique opportunity to reduce animal use in studying the aetiology of neurodevelopmental disorders (NDD), such as schizophrenia (SZ) and Autism Spectrum Disorder (ASD). Their capacity to differentiate into specific neuronal cell types allows researchers to observe human neural development under normal conditions, but also under the influence of disease-causing agents. To date however, the majority of such studies have focussed only on either genetic or environmental drivers of disease. In fact, gene x environment interactions are thought to be critical in shaping an individuals risk for developing NDD and the likely clinical outcome, particularly if the interactions occur during critical periods of fetal brain development. Therefore, if hIPSC are to truly deliver on their potential, the challenge is to use them to study the combination of genetic and environmental disease risk factors, ideally in a cell specific manner, which has the potential to be a highly relevant model to study the biological causes of NDD using a human model system.

In this context, both epidemiology and animal models provide evidence for a link between maternal immune activation (MIA) during pregnancy and increased risk for NDD (including ASD and SZ), in the affected offspring. Despite this, several key gaps in our knowledge remain. First, how does MIA affect human neural developmental at the genomic and epigenomic level? Second, how do these influences map onto known genetic risk mechanisms associated with NDD? For example, is the effect of MIA via an influence on high confidence genes associated with NDD? If so, what classes of genetic variants are then most highly affected? Furthermore, can MIA induce pathological changes in gene expression in the developing brain that shares similarities with gene expression dysregulation found in both children and adults with NDD? Conversely, what gene expression pathology is present in the MIA-exposed developing brain that is absent in older children and adults with NDD? Finally, can we identify specific mechanistic pathways that MIA impacts on that are highly relevant for NDD?

Whilst studies in animal models have gone a long way to addressing some of these questions, there is a pressing need to translate these findings into human model systems. This is due to critical species differences in the development of human and animal brains, both in terms of gene regulatory networks and cellular proliferative behaviour. Therefore, we propose to develop a human cellular model of MIA using hIPSC, which can be applied to neural progenitor cells (NPCs) derived from keratinocytes obtained from healthy controls and individuals with highly penetrant disease-causing mutations for NDD such as major deletions in the chromsome 22q region, which confer risk for ASD and SZ. This in vitro approach will provide a robust human cell-based model of MIA, which can replace a large number of animal models that are the only currently available alternative. In doing so, our proposal will deliver the following impacts:

(1) Broaden the potential of hIPSCs in gene x environment interaction modelling, leading to a significant reduction in the number of rodents and non-human primates used in MIA models.

(2) Establish the relevance of the extant animal data for human health and disease.

(3) Elucidate causal and human relevant molecular and cellular mechanisms driving the adverse effects of MIA on human neocortical development, increasing our understanding of key mechanistic links as to how MIA may confer risk for later development of NDD.

(4) Accelerate the development of potential therapeutic targets for specific environmental risk factors that may be more amenable to prevention and/or treatment later in life, than genetic etiologies.