Department of Neuroscience, Karolinska Institutet, 171 77, Stockholm, Sweden.
Department of Women's and Children's Health, 171 77, Stockholm, Sweden.
Transl Psychiatry. 2023 Jul 13;13(1):258. doi: 10.1038/s41398-023-02560-w.
Central nervous system (CNS) tumors account for almost a third of pediatric cancers and are the largest contributor to cancer-related death in children. Cranial radiation therapy (CRT) is, often in combination with chemotherapy and surgery, effective in the treatment of high-grade childhood brain cancers, but it has been associated with late complications in 50-90% of survivors, such as decline in cognition and mood, decreased social competence, and fatigue. A leading hypothesis to explain the decline in cognition, at least partially, is injury to the neural stem and progenitor cells (NSPCs), which leads to apoptosis and altered fate choice, favoring gliogenesis over neurogenesis. Hence, treatments harnessing neurogenesis are of great relevance in this context. Lithium, a well-known mood stabilizer, has neuroprotective and antitumor effects and has been found to reverse irradiation-induced damage in rodents, at least in part by regulating the expression of the glutamate decarboxylase 2 gene (Gad2) via promoter demethylation in rat NSPCs. Additionally, lithium was shown to rescue irradiation-induced cognitive defects in mice. Here, we show that irradiation (IR) alone or in combination with lithium chloride (LiCl) caused major changes in gene expression and global DNA methylation in iPSC-derived human NSPCs (hNSPCs) compared to untreated cells, as well as LiCl-only-treated cells. The pattern of DNA methylation changes after IR-treatment alone was stochastic and observed across many different gene groups, whereas differences in DNA methylation after LiCl-treatment of irradiated cells were more directed to specific promoters of genes, including genes associated with neurogenesis, for example GAD2. Interestingly, IR and IR + LiCl treatment affected the promoter methylation and expression of several genes encoding factors involved in BMP signaling, including the BMP antagonist gremlin1. We propose that lithium in addition to promoting neuronal differentiation, also represses glial differentiation in hNSPCs with DNA methylation regulation being a key mechanism of action.
中枢神经系统（CNS）肿瘤占儿童癌症的近三分之一，是导致儿童癌症相关死亡的最大原因。颅放射治疗（CRT）常与化疗和手术联合用于治疗高级别儿童脑癌，但它与 50-90%幸存者的迟发性并发症有关，如认知和情绪下降、社交能力下降和疲劳。一个主要的假说解释了认知能力的下降，至少部分是由于神经干细胞和祖细胞（NSPCs）的损伤，导致细胞凋亡和命运选择改变，有利于神经胶质生成而不是神经发生。因此，在这种情况下，利用神经发生的治疗方法具有重要意义。锂是一种众所周知的情绪稳定剂，具有神经保护和抗肿瘤作用，已被发现可通过调节谷氨酸脱羧酶 2 基因（Gad2）在大鼠 NSPCs 中的启动子去甲基化，至少部分逆转照射诱导的损伤。此外，锂还可以挽救照射诱导的小鼠认知缺陷。在这里，我们显示，与未经处理的细胞相比，照射（IR）单独或与氯化锂（LiCl）联合处理会导致 iPSC 衍生的人类 NSPCs（hNSPCs）中的基因表达和全基因组 DNA 甲基化发生重大变化，以及单独用 LiCl 处理的细胞。IR 单独处理后 DNA 甲基化变化的模式是随机的，并且在许多不同的基因群中观察到，而照射后 LiCl 处理的细胞中 DNA 甲基化的差异更指向特定基因的启动子，包括与神经发生相关的基因，例如 GAD2。有趣的是，IR 和 IR+LiCl 处理影响了几个参与 BMP 信号转导的基因的启动子甲基化和表达，包括 BMP 拮抗剂 gremlin1。我们提出，除了促进神经元分化外，锂还通过 DNA 甲基化调节抑制 hNSPCs 中的神经胶质分化，这是一种关键的作用机制。
