Chorioamnionitis accelerates granule cell and oligodendrocyte maturation in the cerebellum of preterm nonhuman primates.
Chorioamnionitis accelerates granule cell and oligodendrocyte maturation in the cerebellum of preterm nonhuman primates.
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DOI：
10.1186/s12974-024-03012-y
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发表时间：
2024-01-10
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
早产通常与绒毛膜炎有关，并导致神经发育障碍的风险增加，如自闭症。早产可导致小脑发育不全，但早产儿小脑发育中断的机制尚不清楚。小脑在自闭症谱系障碍患者中一直受到影响，表现为浦肯野细胞减少，小脑灰质减少和连接改变。将早产恒河猴胎儿暴露于羊膜内LPS（1 mg，E. coliO 55：B5），注射后5天剖腹产。采集母体和胎儿血浆用于细胞因子测量。通过流式细胞术分析绒毛膜-蜕膜的免疫细胞群。在10×铬平台上通过单核RNA测序（snRNA-seq）对胎儿小脑进行组织学和分子分析。分析snRNA-seq数据的细胞群体、细胞类型特异性基因表达和推断的细胞通讯的差异。 我们在临床相关的绒毛膜炎和早产的恒河猴模型中利用小脑的snRNA-seq，以表明绒毛膜炎导致浦肯野细胞损失并破坏妊娠晚期胎儿小脑中颗粒细胞和少突胶质细胞的成熟。浦肯野细胞损失伴随着从浦肯野细胞到颗粒细胞（其显示加速成熟）和到少突胶质细胞（其显示从前少突胶质细胞加速成熟为髓鞘生成少突胶质细胞）的音刺猬信号传导减少。这些发现表明绒毛膜炎对早产相关的小脑成熟破坏和早产儿神经发育障碍的发病机制有一定作用。在线版本包含补充材料，可通过10.1186/s12974-024-03012-y获得。
Preterm birth is often associated with chorioamnionitis and leads to increased risk of neurodevelopmental disorders, such as autism. Preterm birth can lead to cerebellar underdevelopment, but the mechanisms of disrupted cerebellar development in preterm infants are not well understood. The cerebellum is consistently affected in people with autism spectrum disorders, showing reduction of Purkinje cells, decreased cerebellar grey matter, and altered connectivity. Preterm rhesus macaque fetuses were exposed to intra-amniotic LPS (1 mg, E. coli O55:B5) at 127 days (80%) gestation and delivered by c-section 5 days after injections. Maternal and fetal plasma were sampled for cytokine measurements. Chorio-decidua was analyzed for immune cell populations by flow cytometry. Fetal cerebellum was sampled for histology and molecular analysis by single-nuclei RNA-sequencing (snRNA-seq) on a 10× chromium platform. snRNA-seq data were analyzed for differences in cell populations, cell-type specific gene expression, and inferred cellular communications. We leveraged snRNA-seq of the cerebellum in a clinically relevant rhesus macaque model of chorioamnionitis and preterm birth, to show that chorioamnionitis leads to Purkinje cell loss and disrupted maturation of granule cells and oligodendrocytes in the fetal cerebellum at late gestation. Purkinje cell loss is accompanied by decreased sonic hedgehog signaling from Purkinje cells to granule cells, which show an accelerated maturation, and to oligodendrocytes, which show accelerated maturation from pre-oligodendrocytes into myelinating oligodendrocytes. These findings suggest a role of chorioamnionitis on disrupted cerebellar maturation associated with preterm birth and on the pathogenesis of neurodevelopmental disorders among preterm infants. The online version contains supplementary material available at 10.1186/s12974-024-03012-y.
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影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
11.4
作者：
Oksenberg, Nir;Ahituv, Nadav
通讯作者：
Ahituv, Nadav
影响因子：
6.2
作者：
Broek JA;Guest PC;Rahmoune H;Bahn S
通讯作者：
Bahn S
影响因子：
3.5
作者：
Fatemi, S. Hossein;Aldinger, Kimberly A.;Ashwood, Paul;Bauman, Margaret L.;Blaha, Charles D.;Blatt, Gene J.;Chauhan, Abha;Chauhan, Ved;Dager, Stephen R.;Dickson, Price E.;Estes, Annette M.;Goldowitz, Dan;Heck, Detlef H.;Kemper, Thomas L.;King, Bryan H.;Martin, Loren A.;Millen, Kathleen J.;Mittleman, Guy;Mosconi, Matthew W.;Persico, Antonio M.;Sweeney, John A.;Webb, Sara J.;Welsh, John P.
通讯作者：
Welsh, John P.