CSF exosomal miRNAs impact on neural stem cell differentiation contributing to a premature neuro-glial switch following haemorrhage in the developing brain

The microenvironment of the neural stem/progenitor cells (NSPCs) can influence their fate during cortical development. Cerebrospinal fluid (CSF), that runs along the lateral ventricle walls, provides factors which support the division, development, and migration of the surrounding NSPCs. Alterations in CSF composition (growth factors, hormones, miRNAs) after a brain injury can cause the deregulation of NSPCs homeostasis and contribute to central nervous system implications. While there are many studies about adult NSPCs-CSF interaction after an intraventricular haemorrhage (IVH) in adults, less is known about this interaction during development. We hypothesised that the miRNA CSF’s content may alter after IVH, and this can affect NSPCs fate. We tested 2.083 miRNAs in the CSF from 10 preterm infants with intraventricular haemorrhage (IVH-CSF) by HTG EdgeSeq miRNA whole transcriptome assay. We identified 587 differentially expressed miRNAs (DESeq tool, Reveal Software) and 9 miRNA families with at least three differentially expressed family members (miRViz tool). The deregulated miRNAs are involved in processes such as cell survival, proliferation and differentiation, metabolism, inflammation, and reactive gliosis. In functional in vitro assays, we showed that exosomal miRNAs extracted from IVH-CSF shifted the differentiation of human fetal neural stem cells towards astrocytes. These results provide first insight into potential mechanisms of CSF-NSPCs interactions during brain development guiding reactive gliosis following perinatal brain injury