Neuroimmunology Unit, Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
Department of Microbiology and Immunology, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
J Neuroinflammation. 2023 May 30;20(1):132. doi: 10.1186/s12974-023-02809-7.
Microglia are tissue resident macrophages with a wide range of critically important functions in central nervous system development and homeostasis.
In this study, we aimed to characterize the transcriptional landscape of ex vivo human microglia across different developmental ages using cells derived from pre-natal, pediatric, adolescent, and adult brain samples. We further confirmed our transcriptional observations using ELISA and RNAscope.
We showed that pre-natal microglia have a distinct transcriptional and regulatory signature relative to their post-natal counterparts that includes an upregulation of phagocytic pathways. We confirmed upregulation of CD36, a positive regulator of phagocytosis, in pre-natal samples compared to adult samples in situ. Moreover, we showed adult microglia have more pro-inflammatory signature compared to microglia from other developmental ages. We indicated that adult microglia are more immune responsive by secreting increased levels of pro-inflammatory cytokines in response to LPS treatment compared to the pre-natal microglia. We further validated in situ up-regulation of IL18 and CXCR4 in human adult brain section compared to the pre-natal brain section. Finally, trajectory analysis indicated that the transcriptional signatures adopted by microglia throughout development are in response to a changing brain microenvironment and do not reflect predetermined developmental states.
In all, this study provides unique insight into the development of human microglia and a useful reference for understanding microglial contribution to developmental and age-related human disease.
小胶质细胞是组织驻留巨噬细胞，在中枢神经系统发育和稳态中具有广泛的至关重要的功能。
在这项研究中，我们旨在使用源自产前、儿科、青少年和成人脑样本的细胞，描述不同发育年龄的体外人小胶质细胞的转录组特征。我们进一步使用 ELISA 和 RNAscope 验证了我们的转录观察结果。
我们表明，与产后相比，产前小胶质细胞具有独特的转录和调控特征，包括吞噬途径的上调。我们在原位证实了产前样本中 CD36（吞噬作用的正调节剂）的上调，与成人样本相比。此外，与其他发育年龄的小胶质细胞相比，成人小胶质细胞具有更具促炎的特征。我们表明，与产前小胶质细胞相比，成人小胶质细胞在受到 LPS 处理时分泌更多的促炎细胞因子，具有更高的免疫反应性。我们进一步验证了在人类成年脑切片中与产前脑切片相比，IL18 和 CXCR4 的原位上调。最后，轨迹分析表明，小胶质细胞在整个发育过程中采用的转录特征是对不断变化的脑微环境的反应，而不是反映预先确定的发育状态。
总之，这项研究为理解小胶质细胞对发育和年龄相关的人类疾病的贡献提供了对人类小胶质细胞发育的独特见解和有用的参考。
