Department of Anatomy and Cell Biology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi 466-8550, Japan
Department of Anatomy and Cell Biology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi 466-8550, Japan.
J Neurosci. 2022 Jan 19;42(3):362-376. doi: 10.1523/JNEUROSCI.1201-21.2021. Epub 2021 Nov 24.
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 pericyte depletion induced by the intraventricular administration of a neutralizing antibody against platelet-derived growth factor receptor (PDGFR)β (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, coculture of isolated CD11b microglia and NG2PDGFRα 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. This study highlights the novel effect of pericytes on microglia in the developing mouse brain. Through multiple analyses using an pericyte depletion mouse model and an coculture study of isolated pericytes and microglia from parenchymal cells, we demonstrated that pericytes contribute to microglial proliferation and support microglia in efficiently promoting the differentiation of neural stem cells into intermediate progenitors. Our present data provide evidence that pericytes function not only in the maintenance of cerebral microcirculation and blood brain barrier (BBB) integrity but also in microglial homeostasis in the developing cerebral walls. These findings will expand our knowledge and help elucidate the mechanism of brain development both in healthy and disease conditions.
在发育中的大脑中，小胶质细胞具有多方面的功能，例如促进神经祖细胞的分化，并有助于神经元的定位和存活。虽然先前的研究已经注意到了发育中的大脑内皮细胞与小胶质细胞之间的关系，但对围绕内皮细胞的周细胞的重要性却关注甚少。在这项研究中，我们试图剖析周细胞在发育中的小鼠大脑中小胶质细胞分布和功能中的作用。我们的免疫组织化学分析表明，约有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，小胶质细胞优先与覆盖总毛细血管表面积 79.8%的周细胞相关。通过向脑室中注射抗血小板衍生生长因子受体（PDGFR）β的中和抗体（克隆 APB5）来耗尽周细胞，我们发现与对照抗体处理的大脑相比，小胶质细胞密度明显降低，这是由于它们的增殖能力较低。此外，从实质细胞中分离出的 CD11b 小胶质细胞和 NG2PDGFRα 细胞（主要由周细胞组成）的共培养表明，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 处理耗尽周细胞会导致小胶质细胞无法促进神经干细胞分化为中间祖细胞。总之，我们的研究结果表明，周细胞有助于发育中的大脑中小胶质细胞的稳态，从而间接支持小胶质细胞对神经祖细胞的影响。这项研究强调了周细胞在发育中的小鼠大脑中小胶质细胞中的新作用。通过使用周细胞耗竭小鼠模型进行的多项分析以及对来自实质细胞的分离周细胞和小胶质细胞的共培养研究，我们证明了周细胞有助于小胶质细胞的增殖，并支持小胶质细胞有效地促进神经干细胞分化为中间祖细胞。我们目前的数据提供了证据，证明周细胞不仅在维持大脑微循环和血脑屏障（BBB）完整性方面起作用，而且在发育中的脑壁中小胶质细胞的稳态中也起作用。这些发现将扩展我们的知识，并有助于阐明健康和疾病状态下的大脑发育机制。
