Gialeli Andriana, Spaull Robert, Plösch Torsten, Uney James, Llana Oscar Cordero, Heep Axel
School of Medicine and Health Science, Research Centre Neurosensory Science, University of Oldenburg, Oldenburg, Germany.
Bristol Medical School, Translational Health Sciences, Dorothy Hodgkin Building, University of Bristol, Bristol, United Kingdom.
Front Mol Neurosci. 2023 Sep 18;16:1211373. doi: 10.3389/fnmol.2023.1211373. eCollection 2023.
Germinal Matrix-Intraventricular Haemorrhage (GM-IVH) is one of the most common neurological complications in preterm infants, which can lead to accumulation of cerebrospinal fluid (CSF) and is a major cause of severe neurodevelopmental impairment in preterm infants. However, the pathophysiological mechanisms triggered by GM-IVH are poorly understood. Analyzing the CSF that accumulates following IVH may allow the molecular signaling and intracellular communication that contributes to pathogenesis to be elucidated. Growing evidence suggests that miRs, due to their key role in gene expression, have a significant utility as new therapeutics and biomarkers.
The levels of 2,083 microRNAs (miRs) in 15 CSF samples from 10 infants with IVH were measured using miRNA whole transcriptome sequencing. Gene ontology (GO) and miR family analysis were used to uncover dysregulated signalling which were then validated in vitro in human foetal neural progenitor cells treated with IVH-CSF.
Five hundred eighty-seven miRs were differentially expressed in the CSF extracted at least 2 months after injury, compared to CSF extracted within the first month of injury. GO uncovered key pathways targeted by differentially expressed miRs including the MAPK cascade and the JAK/STAT pathway. Astrogliosis is known to occur in preterm infants, and we hypothesized that this could be due to abnormal CSF-miR signaling resulting in dysregulation of the JAK/STAT pathway - a key controller of astrocyte differentiation. We then confirmed that treatment with IVH-CSF promotes astrocyte differentiation from human fetal NPCs and that this effect could be prevented by JAK/STAT inhibition. Taken together, our results provide novel insights into the CSF/NPCs crosstalk following perinatal brain injury and reveal novel targets to improve neurodevelopmental outcomes in preterm infants.
生发基质-脑室内出血（GM-IVH）是早产儿最常见的神经并发症之一，可导致脑脊液（CSF）积聚，是早产儿严重神经发育障碍的主要原因。然而，GM-IVH引发的病理生理机制尚不清楚。分析IVH后积聚的脑脊液可能有助于阐明导致发病机制的分子信号和细胞内通讯。越来越多的证据表明，由于miR在基因表达中起关键作用，它们作为新的治疗方法和生物标志物具有重要用途。
使用miRNA全转录组测序测量了10例IVH婴儿的15份脑脊液样本中2083种微小RNA（miR）的水平。基因本体（GO）和miR家族分析用于发现失调的信号传导，然后在用人IVH-CSF处理的人胎儿神经祖细胞中进行体外验证。
与损伤后第一个月内提取的脑脊液相比，在损伤后至少2个月提取的脑脊液中，有587种miR差异表达。GO揭示了差异表达miR靶向的关键途径，包括MAPK级联反应和JAK/STAT途径。已知早产儿会发生星形胶质细胞增生，我们推测这可能是由于脑脊液-miR信号异常导致JAK/STAT途径失调所致，而JAK/STAT途径是星形胶质细胞分化的关键控制器。然后我们证实，用IVH-CSF处理可促进人胎儿神经祖细胞向星形胶质细胞分化，并且这种作用可通过抑制JAK/STAT来预防。总之，我们的结果为围产期脑损伤后脑脊液/神经祖细胞的相互作用提供了新的见解，并揭示了改善早产儿神经发育结局的新靶点。
