Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2021 Apr 13;118(15). doi: 10.1073/pnas.2005483118.
Copy number variation (CNV) at the 16p11.2 locus is associated with neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia. CNVs of the 16p gene can manifest in opposing head sizes. Carriers of 16p11.2 deletion tend to have macrocephaly (or brain enlargement), while those with 16p11.2 duplication frequently have microcephaly. Increases in both gray and white matter volume have been observed in brain imaging studies in 16p11.2 deletion carriers with macrocephaly. Here, we use human induced pluripotent stem cells (hiPSCs) derived from controls and subjects with 16p11.2 deletion and 16p11.2 duplication to understand the underlying mechanisms regulating brain overgrowth. To model both gray and white matter, we differentiated patient-derived iPSCs into neural progenitor cells (NPCs) and oligodendrocyte progenitor cells (OPCs). In both NPCs and OPCs, we show that CD47 (a "don't eat me" signal) is overexpressed in the 16p11.2 deletion carriers contributing to reduced phagocytosis both in vitro and in vivo. Furthermore, 16p11.2 deletion NPCs and OPCs up-regulate cell surface expression of calreticulin (a prophagocytic "eat me" signal) and its binding sites, indicating that these cells should be phagocytosed but fail to be eliminated due to elevations in CD47. Treatment of 16p11.2 deletion NPCs and OPCs with an anti-CD47 antibody to block CD47 restores phagocytosis to control levels. While the CD47 pathway is commonly implicated in cancer progression, we document a role for CD47 in psychiatric disorders associated with brain overgrowth.
16p11.2 基因座的拷贝数变异 (CNV) 与神经精神疾病有关，如自闭症谱系障碍和精神分裂症。16p 基因的 CNV 可表现为头围大小相反。16p11.2 缺失的携带者往往头围较大（或大脑增大），而 16p11.2 重复的携带者则经常头围较小。在头围较大的 16p11.2 缺失携带者的脑成像研究中观察到灰质和白质体积增加。在这里，我们使用来自对照和 16p11.2 缺失和 16p11.2 重复患者的人诱导多能干细胞 (hiPSC) 来了解调节大脑过度生长的潜在机制。为了模拟灰质和白质，我们将患者来源的 iPSC 分化为神经祖细胞 (NPC) 和少突胶质祖细胞 (OPC)。在 NPC 和 OPC 中，我们发现 CD47（一种“不要吃我”信号）在 16p11.2 缺失携带者中过度表达，导致体外和体内吞噬作用减少。此外，16p11.2 缺失 NPC 和 OPC 上调细胞表面钙网蛋白（一种促吞噬“吃我”信号）及其结合位点的表达，表明这些细胞应该被吞噬，但由于 CD47 的升高而未能被消除。用抗 CD47 抗体阻断 CD47 治疗 16p11.2 缺失 NPC 和 OPC 可将吞噬作用恢复到对照水平。虽然 CD47 途径通常与癌症进展有关，但我们证明了 CD47 在与大脑过度生长相关的神经精神疾病中的作用。
