Localized microglia dysregulation impairs central nervous system myelination in development.
Localized microglia dysregulation impairs central nervous system myelination in development.
复制标题
DOI：
10.1186/s40478-023-01543-8
复制
发表时间：
2023-03-22
影响因子：
7.1
通讯作者：
中科院分区：
文献类型：
--
作者：
神经元轴突的髓鞘形成是中枢神经系统发育和功能的关键方面。然而，影响人类发育髓鞘形成及其失败的基本细胞和分子机制尚未完全了解。在这里，我们使用了一个罕见的人类发育白色物质库的数字空间转录组学来揭示局部先天免疫反应失调与髓鞘形成受阻有关。我们发现，髓鞘形成不良的地区有一个独特的签名II型干扰素信号在小胶质细胞/巨噬细胞，相对于相邻的髓鞘形成地区。这与成熟的少突胶质细胞的惊人增加有关，少突胶质细胞不能适当地形成髓鞘过程。我们在功能上将这些发现联系起来，表明干扰素刺激的小胶质细胞的条件培养基足以使培养中的少突胶质细胞的髓鞘过程形成失调。我们确定了II型干扰素诱导剂骨桥蛋白（SPP 1）在髓鞘形成不良的大脑中上调，这表明它是一种潜在的生物标志物。我们的研究结果揭示了小胶质细胞-成熟少突胶质细胞相互作用和干扰素信号在调节发育中的人脑髓鞘形成中的重要性。在线版本包含补充材料，可通过10.1186/s40478 - 023 - 01543 - 8获得。
Myelination of neuronal axons is a critical aspect of central nervous system development and function. However, the fundamental cellular and molecular mechanisms influencing human developmental myelination and its failure are not fully understood. Here, we used digital spatial transcriptomics of a rare bank of human developing white matter to uncover that a localized dysregulated innate immune response is associated with impeded myelination. We identified that poorly myelinating areas have a distinct signature of Type II interferon signalling in microglia/macrophages, relative to adjacent myelinating areas. This is associated with a surprising increase in mature oligodendrocytes, which fail to form myelin processes appropriately. We functionally link these findings by showing that conditioned media from interferon-stimulated microglia is sufficient to dysregulate myelin process formation by oligodendrocytes in culture. We identify the Type II interferon inducer, Osteopontin (SPP1), as being upregulated in poorly myelinating brains, indicating a potential biomarker. Our results reveal the importance of microglia-mature oligodendrocyte interaction and interferon signaling in regulating myelination of the developing human brain. The online version contains supplementary material available at 10.1186/s40478-023-01543-8.
影响因子：
4
作者：
Boardman JP;Ireland G;Sullivan G;Pataky R;Fleiss B;Gressens P;Miron V
通讯作者：
Miron V