Stress-induced alterations in neurodevelopment in iPSC-Derived in vitro model systems

Psychological stress is common in women during pregnancy and after childbirth, showing a prevalence of up to 15.6% in pregnant women in developing countries. Clinical and pre-clinical studies have implicated their role in negatively affecting pregnancy outcomes and have been linked to adverse child outcomes. Yet the underlying mechanisms remain poorly understood, specifically the signatures associated with their effect on human fetal development. Thereby, impairing our further understanding of the effects of therapeutics used to treat these disorders in expecting mothers. This study proposes the use of human iPSC-derived embryoid bodies (EBs) and forebrain-specific organoids as complementary human developmental models to investigate the effects of exposure to prenatal stress (mediated by glucocorticoids) across distinct stages, in vitro . Our findings suggested that excessive glucocorticoids altered early lineage specification in an exposure-dependent manner. This was evidenced by a brief increase in pluripotent and neural progenitor populations, with mild alterations in proliferative dynamics without a net change in proliferative capacity. Changes in lineage-associated markers were observed in ectodermal and meso-endodermal layers of EBs. Particularly, focusing on neurogenesis (forebrain-specific organoids) to understand the impact of stress on neurodevelopment, we saw concentration-dependent changes in progenitor maintenance and neuronal- glial differentiation. Furthermore, the activation of inflammatory and oxidative stress responses can be implicated as signalling mechanisms responsible for the differences observed. Together, these results suggest that glucocorticoid signalling linked to prenatal stress can alter developmental trajectories by modifying cellular states rather than directly altering proliferation or survival during early development.