The miRNA transcriptome of cerebrospinal fluid in preterm infants reveals the signaling pathways that promote reactive gliosis following cerebral hemorrhage.
The miRNA transcriptome of cerebrospinal fluid in preterm infants reveals the signaling pathways that promote reactive gliosis following cerebral hemorrhage.
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DOI：
10.3389/fnmol.2023.1211373
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发表时间：
2023
影响因子：
4.8
通讯作者：
Heep, Axel
中科院分区：
文献类型：
--
作者：
Gialeli, Andriana;Spaull, Robert;Ploesch, Torsten;Uney, James;Llana, Oscar Cordero;Heep, Axel
关键词：
生发基质脑室内出血（GM-IVH）是早产儿最常见的神经系统并发症之一，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，人们对 GM-IVH 引发的病理生理机制知之甚少。分析 IVH 后积累的脑脊液可能有助于阐明有助于发病机制的分子信号传导和细胞内通讯。越来越多的证据表明，miR 由于其在基因表达中的关键作用，作为新的治疗方法和生物标志物具有重要的用途。使用 miRNA 全转录组测序测量了 10 名 IVH 婴儿的 15 个脑脊液样本中 2,083 个 microRNA (miR) 的水平。使用基因本体论 (GO) 和 miR 家族分析来揭示失调的信号传导，然后在用 IVH-CSF 处理的人胎儿神经祖细胞中进行体外验证。与损伤第一个月内提取的脑脊液相比，损伤后至少 2 个月提取的脑脊液中有 587 个 miR 存在差异表达。 GO 发现了差异表达 miR 靶向的关键通路，包括 MAPK 级联和 JAK/STAT 通路。已知星形胶质细胞增生症发生在早产儿中，我们假设这可能是由于 CSF-miR 信号异常导致 JAK/STAT 通路（星形胶质细胞分化的关键控制器）失调所致。然后我们证实，IVH-CSF 治疗可促进人胎儿 NPC 的星形胶质细胞分化，并且这种效应可以通过 JAK/STAT 抑制来预防。总而言之，我们的结果为围产期脑损伤后的 CSF/NPC 串扰提供了新的见解，并揭示了改善早产儿神经发育结果的新目标。
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.
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影响因子：
4.6
作者：
Bhomia M;Balakathiresan NS;Wang KK;Papa L;Maheshwari RK
通讯作者：
Maheshwari RK
影响因子：
16.2
作者：
Lehtinen MK;Zappaterra MW;Chen X;Yang YJ;Hill AD;Lun M;Maynard T;Gonzalez D;Kim S;Ye P;D'Ercole AJ;Wong ET;LaMantia AS;Walsh CA
通讯作者：
Walsh CA
影响因子：
5.1
作者：
Dangla-Valls, Adria;Molinuevo, Jose Luis;Antonell, Anna
通讯作者：
Antonell, Anna
影响因子：
5.2
作者：
LEVENE, MI;STARTE, DR
通讯作者：
STARTE, DR
影响因子：
4.3
作者：
Cha, Diana J.;Mengel, David;Walsh, Dominic M.
通讯作者：
Walsh, Dominic M.