Signaling to the immature brain - Choroid plexus, insulin-like growth factor 1 and extracellular vesicles

Sammanfattning: Extremely preterm infants (i.e., born below 28 gestational weeks), are at high risk of developing brain morbidities including intraventricular hemorrhage (IVH) and neurodevelopmental impairment. Despite over 50 years of research, there is currently no effective therapy available for preventing IVH. Insulin-like growth factor 1 (IGF-1) plays a pivotal role in perinatal development. Extremely preterminfants exhibit reduced levels of circulatory IGF-1, and low levels of IGF-1 during perinatal development are associated with poor weight gain, reduced brain volumes and impaired cognitive development. While clinical data suggest that supplementary treatment with IGF-1, aimed at restoring physiologicallevels, could potentially enhance neurodevelopment, the precise molecular mechanisms underlying the protective effects remain incompletely understood.One potential transport mechanism of blood-borne IGF-1 to reach the central nervous system is via the choroid plexus (ChP). All ventricles in the brain contain this tissue, which is the main producer of cerebrospinal fluid (CSF). By studying the onset of IVH using our experimental preterm rabbit pup model,we have discovered that ChP is the predominant site of bleeding in IVH in our model.In this thesis work, we have investigated i) the interaction of blood-borne IGF-1 on the ChP in the immature brain, and ii) the impact of IGF-1 on the occurrence of IVH in an experimental model of IVH. Our findings reveal that blood-borne IGF-1 accumulates in the ChP following systemic administration ofIGF-1, leading to an upregulation of genes associated with vascular maturation in the ChP. Furthermore, we observed that uptake of administrated IGF-1 from the circulation and CSF was dependent onpostnatal age. Through a combination of an in vitro cell culture system and a preterm rabbit pup model, we provide evidence for an extracellular vesicle (EV)-mediated transport of blood-borne IGF-1 through the ChP, andinto the CSF. Ultimately, the IGF-1 carrying vesicles reach the deep layers of the hippocampus in the immature brain. Finally, we evaluated the potential of IGF-1 to prevent IVH in a preterm rabbit pup model. Altogether, the results presented in this thesis highlight the importance of the ChP and IGF-1 in thedeveloping brain. More research is needed to fully understand the interaction between IGF-1 and the ChP, to disclose the EV-mediated signaling via the ChP, and to clarify the potential preventive effects of IGF-1 on development of IVH.