Embryonic Pericytes Promote Microglial Homeostasis and Their Effects on Neural Progenitors in the Developing Cerebral Cortex
Embryonic Pericytes Promote Microglial Homeostasis and Their Effects on Neural Progenitors in the Developing Cerebral Cortex
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DOI：
10.1523/jneurosci.1201-21.2021
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发表时间：
2022-01-19
影响因子：
5.3
通讯作者：
Miyata, Takaki
中科院分区：
文献类型：
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作者：
Hattori, Yuki;Itoh, Haruka;Miyata, Takaki
在发育中的大脑中，小胶质细胞的多方面功能，如促进神经前体细胞的分化，有助于神经元的定位和存活，已经逐渐被揭示。虽然之前的研究已经注意到血管内皮细胞和小胶质细胞在发育中的大脑之间的关系，但很少有人注意到周细胞的重要性，周细胞是内皮细胞周围的壁细胞。在这项研究中，我们试图剖析周细胞在小鼠大脑发育过程中小胶质细胞的分布和功能中的作用。我们的免疫组织化学分析显示，大约一半的小胶质细胞附着在脑壁的毛细血管上。值得注意的是，对小胶质细胞、血管内皮细胞和周细胞位置的放大观察表明，小胶质细胞优先与周细胞联系，周细胞占总毛细血管表面积的79.8%。通过脑室注射抗血小板衍生生长因子受体(PDGFR)b中和抗体(克隆APB5)引起的周细胞耗竭，我们发现小胶质细胞密度明显低于对照组抗体处理组的小胶质细胞密度，原因是小胶质细胞的增殖能力低。此外，从实质细胞分离的CD11b+小胶质细胞和NG2+PDGFRA-细胞在体外共培养表明，周细胞通过产生可溶性因子促进小胶质细胞的增殖。此外，APB5处理导致周细胞耗尽，导致小胶质细胞无法促进神经干细胞分化为中间前体细胞。综上所述，我们的发现表明，周细胞促进发育中的大脑中小胶质细胞的动态平衡，从而间接支持小胶质细胞对神经前体细胞的影响。
Multifaceted microglial functions in the developing brain, such as promoting the differentiation of neural progenitors and contributing to the positioning and survival of neurons, have been progressively revealed. Although previous studies have noted the relationship between vascular endothelial cells and microglia in the developing brain, little attention has been given to the importance of pericytes, the mural cells surrounding endothelial cells. In this study, we attempted to dissect the role of pericytes in microglial distribution and function in developing mouse brains. Our immunohistochemical analysis showed that approximately half of the microglia attached to capillaries in the cerebral walls. Notably, a magnified observation of the position of microglia, vascular endothelial cells and pericytes demonstrated that microglia were preferentially associated with pericytes that covered 79.8% of the total capillary surface area. Through in vivo pericyte depletion induced by the intraventricular administration of a neutralizing antibody against platelet-derived growth factor receptor (PDGFR)b (clone APB5), we found that microglial density was markedly decreased compared with that in control antibody-treated brains because of their low proliferative capacity. Moreover, in vitro coculture of isolated CD11b+ microglia and NG2+PDGFRa- cells, which are mostly composed of pericytes, from parenchymal cells indicated that pericytes promote microglial proliferation via the production of soluble factors. Furthermore, pericyte depletion by APB5 treatment resulted in a failure of microglia to promote the differentiation of neural stem cells into intermediate progenitors. Taken together, our findings suggest that pericytes facilitate microglial homeostasis in the developing brains, thereby indirectly supporting microglial effects on neural progenitors.