Wei, Jingzhang; (2022) iPS modelling of early life stress via glucocorticoid receptors: consequences for microglia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Prenatal exposure to glucocorticoids (GCs) is one type of early life (ELS) stress linked to an increased risk of later-life psychiatric and neurodevelopmental disorders. It is becoming increasingly clear that microglia play a significant role in these disorders. There is few, if any, human research on GC exposure during microglial development. An in vitro ELS model was established using continuous exposure of human iPS-microglia to GCs during primitive haematopoiesis (the critical stage of iPS-microglial differentiation); functional assays and RNA-Seq was used to examine how this exposure affected the microglial phenotype as they differentiated and matured into microglia. Over the mineralocorticoid receptor, the iPS-myeloid progenitors and iPS-microglia predominantly expressed glucocorticoid receptor, particularly the GR-α splice variant and differentiation/maturation-related increment of GR 5’ UTR splice variant. We found that chronic exposure to GCs during primitive haematopoiesis could mimic the effects of ELS in vivo. As a result, prolonged pre-exposure to GCs enhanced type I interferon signalling, cGAS micronuclei, cellular senescence, and reduced proliferation in mature iPS microglia. The findings from this in vitro ELS model have ramifications for the responses of microglia in the pathogenesis of GC-mediated ELS-associated disorders such as schizophrenia, attention-deficit hyperactivity disorder and autism spectrum disorder.

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