PDF(Pubmed)
Abstract：
Although microglia are macrophages of the central nervous system, their involvement is not limited to immune functions. The roles of microglia during development in humans remain poorly understood due to limited access to fetal tissue. To understand how microglia can impact human neurodevelopment, the methyl-CpG binding protein 2 (MECP2) gene was knocked out in human microglia-like cells (MGLs). Disruption of the MECP2 in MGLs led to transcriptional and functional perturbations, including impaired phagocytosis. The co-culture of healthy MGLs with MECP2-knockout (KO) neurons rescued synaptogenesis defects, suggesting a microglial role in synapse formation. A targeted drug screening identified ADH-503, a CD11b agonist, restored phagocytosis and synapse formation in spheroid-MGL co-cultures, significantly improved disease progression, and increased survival in MeCP2-null mice. These results unveil a MECP2-specific regulation of human microglial phagocytosis and identify a novel therapeutic treatment for MECP2-related conditions.
摘要：
虽然小胶质细胞是中枢神经系统的巨噬细胞，它们的参与不仅限于免疫功能。由于对胎儿组织的访问有限，小胶质细胞在人类发育过程中的作用仍然知之甚少。为了了解小胶质细胞如何影响人类神经发育，甲基-CpG结合蛋白2(MECP2)基因在人小胶质细胞样细胞(MGLs)中被敲除.MGL中MECP2的破坏导致转录和功能扰动，包括吞噬作用受损。健康MGL与MECP2敲除（KO）神经元的共培养拯救了突触发生缺陷，提示小胶质细胞在突触形成中的作用。靶向药物筛选鉴定了CD11b激动剂ADH-503，球状体-MGL共培养物中恢复的吞噬作用和突触形成，显著改善疾病进展，和增加MeCP2无效小鼠的存活率。这些结果揭示了人类小胶质细胞吞噬作用的MECP2特异性调节，并确定了MECP2相关疾病的新型治疗方法。
