大脑类器官在胶质母细胞瘤中的应用进展

胶质母细胞瘤（GBM）是成人最常见的中枢神经系统恶性肿瘤，具有高度的异质性，瘤内不同细胞和肿瘤微环境之间存在复杂的相互作用。目前体外模型还不能准确再现脑肿瘤微环境，体内原位模型耗时长，成本高昂，且成功率不高。类器官作为一种新型的肿瘤研究模型能够高度模拟原位组织的生理结构和功能，可以稳定地维持肿瘤细胞在体内的特征，已被广泛应用于各种恶性肿瘤的研究。目前已经通过基因编辑技术诱导大脑类器官形成脑肿瘤，用以研究肿瘤发生的早期阶段，GBM干细胞与大脑类器官共培养可建立高通量药物筛选，直接培养建立GBM类器官可用来研究肿瘤的生物学特性及预测治疗反应。该文对大脑类器官进行简要介绍，回顾GBM类器官建立的不同实验技术方法，并对GBM类器官的应用进行了归纳。     

IL-4调控小胶质细胞极化在血管性认知障碍中的作用机制研究进展

血管性痴呆（vascular dementia,VD）的核心症状是认知功能障碍。大脑缺血后小胶质细胞被激活,进而诱导神经炎症反应是血管性认知功能障碍发生的关键。既往部分研究认为,小胶质细胞在病理状态下主要发挥促炎作用,但近年来越来越多的研究发现,小胶质细胞极化后的不同表型可发挥不同的作用,提示小胶质细胞极化在VD机制研究中的重要地位。白细胞介素-4(interleukin-4,IL-4)作为诱导小胶质细胞从促炎的M1表型极化到抗炎的M2表型的重要调节因子,已被证明与学习认知的病理过程密切相关。本文着重对小胶质细胞极化在血管性认知障碍中的研究进展及IL-4在小胶质细胞极化转化过程中的作用机制进行综述,以期为血管性痴呆的治疗提供新的思路。     

嵌合抗原受体T细胞免疫疗法治疗胶质母细胞瘤的研究进展

嵌合抗原受体T细胞（CART）免疫疗法近年来发展迅速,但在以胶质母细胞瘤（GBM）为代表的实体瘤治疗中没有达到理想的效果。该文简要回顾了GBM的治疗现状、CART的治疗原理及有效靶点,并分析其疗效不显著的各种原因,总结目前有希望的改进策略。     

CHI3L1在胶质母细胞瘤中作用的研究进展

几丁质酶-3样蛋白-1(CHI3L1)属于糖基水解酶家族18，在癌细胞的生长、增殖、侵袭、转移、血管生成、肿瘤相关巨噬细胞的激活以及CD4⁺T细胞的Th2极化中起着关键作用。据报道，CHI3L1在胶质母细胞瘤(GBM)中异常表达，并且和GBM的恶性进展及不良预后有关。该文综述了CHI3L1在GBM增殖、侵袭、耐药性、血管生成及免疫抑制中的潜在作用和靶向CHI3L1治疗GBM的研究，为GBM的辅助治疗研究提供策略。 [引用格式:国际神经病学神经外科学杂志, 2022, 49(1): 61-65.]     

CDK4/6抑制剂在治疗脑胶质母细胞瘤中的研究进展

细胞周期素依赖性蛋白激酶在临床上已用于乳腺癌的治疗,其机制是促使抑癌基因Rb磷酸化,使细胞从G1期进入S期。CDK4/6抑制剂可以抑制乳腺癌、头颈癌、非小细胞肺癌等多种恶性肿瘤的活性。胶质母细胞瘤具有复发率高、生存期短、预后差等特点,治疗难度大,而CDK4/6理论上作为胶质母细胞瘤(GBM)治疗的靶点,CDK4/6抑制剂作用于cyclin D-CDK4/6-INK4-Rb通路,也同样可以抑制胶质母细胞瘤。作为有希望治疗胶质母细胞瘤药物,CDK4/6抑制剂在动物实验,肿瘤细胞系等研究中展示了大量的证据证明其对胶质母细胞瘤能产生抑制作用。同时CDK4/6抑制剂其研发方向是寻找预测标志物,探索联合治疗,以试图解决神经胶质母细胞瘤治疗中的耐药性和复发性中的关键问题,为治疗神经胶质瘤的研究提供新方向和思路。     

胶质母细胞瘤

胶质母细胞瘤又称多形性胶质母细胞瘤（GBM）,是星形细胞肿瘤中恶性程度最高的类型,属WHOⅣ级,分为原发性和继发性。其亚型包括巨细胞型胶质母细胞瘤和胶质肉瘤,占神经上皮组织肿瘤的23%;可发生于任何年龄阶段,以45~65岁高发,30岁以下者鲜见;男性明显高于女性。病变好发部位依次为额颞叶、顶叶和枕叶,小脑和基底节极为少见,可同时累及多个脑叶。肿瘤细胞分化差,常为多形性,密度高,异型性明显,核分裂活跃。     

microRNAs调控小胶质细胞极化在神经炎症中的作用

microRNAs(miRNAs)是一类长度约为19-25个核苷酸稳定的内源性小分子非编码RNA,小胶质细胞是广泛分布于中枢神经系统的常驻免疫细胞,miRNAs与小胶质细胞的极化有着密切的关系。本文综述近年来促炎型/抗炎型miRNAs调控小胶质细胞M1型/M2型极化及其在相关炎症介导的神经系统疾病中的研究进展,充分阐明小胶质细胞极化过程中miRNAs调控机制,为寻找治疗与小胶质极化相关炎症介导的神经系统疾病的新靶点提供了有力的理论依据。     

推动胶质细胞瘤的转化医学研究

脑肿瘤是人类高死亡率的肿瘤之一,其中多形性胶质母细胞瘤(glioblastoma muhiforme,GBM)属于WHO Ⅳ级胶质细胞瘤,是成人中最常见的原发性脑肿瘤.GBM呈浸润性生长,以致手术完全切除较为困难,且其具有放、化疗抵抗性,故复发率高,预后较差.     

间充质干细胞在胶质瘤肿瘤微环境中的作用研究进展

胶质瘤为成人最常见的原发性中枢神经系统肿瘤,预后较差,尤其是胶质母细胞瘤,预后最差。胶质瘤通常呈侵袭性生长,很少可以实现全部切除。近年来,研究表明胶质瘤微环境中多种类型的细胞构成复杂的信号网络。胶质瘤及胶质瘤相关免疫细胞（包括树突细胞、巨噬细胞、B淋巴细胞和小胶质细胞）分泌的多种细胞因子、趋化因子、生长因子、肿瘤代谢相关产物相互作用,形成了一个特殊的脑肿瘤免疫抑制微环境。     

BTPCs在胶质母细胞瘤治疗中的研究进展

胶质母细胞瘤(glioblastoma,GBM)是成人神经上皮性肿瘤中恶性程度最高、最具侵袭性、预后最差的肿瘤[1],中位生存期仅12~18.5个月[2]。脑胶质瘤的细胞来源仍众说纷纭,星形胶质细胞、神经干细胞和少突胶质前体细胞等均有可能是胶质瘤的起源细胞[3]。研究表明,高级别胶质瘤更有可能起源于神经干细胞(neural stem cell,NSCs)[4]。     

Deletion of the RNA regulator HuR in tumor-associated microglia and macrophages stimulates anti-tumor immunity and attenuates glioma growth

Glioblastoma is a malignant brain tumor that portends a poor prognosis. Its resilience, in part, is related to a remarkable capacity for manipulating the microenvironment to promote its growth and survival. Microglia/macrophages are prime targets, being drawn into the tumor and stimulated to produce factors that support tumor growth and evasion from the immune system. Here we show that the RNA regulator, HuR, plays a key role in the tumor-promoting response of microglia/macrophages. Knockout (KO) of HuR led to reduced tumor growth and proliferation associated with prolonged survival in a murine model of glioblastoma. Analysis of tumor composition by flow cytometry showed that tumor-associated macrophages (TAMs) were decreased, more polarized toward an M1-like phenotype, and had reduced PD-L1 expression. There was an overall increase in infiltrating CD4⁺ cells, including Th1 and cytotoxic effector cells, and a concomitant reduction in tumor-associated polymorphonuclear myeloid-derived suppressor cells. Molecular and cellular analyses of HuR KO TAMs and cultured microglia showed changes in migration, chemoattraction, and chemokine/cytokine profiles that provide potential mechanisms for the altered tumor microenvironment and reduced tumor growth in HuR KO mice. In summary, HuR is a key modulator of pro-glioma responses by microglia/macrophages through the molecular regulation of chemokines, cytokines, and other factors. Our findings underscore the relevance of HuR as a therapeutic target in glioblastoma.     

Reducing host aldose reductase activity promotes neuronal differentiation of transplanted neural stem cells at spinal cord injury sites and facilitates locomotion recovery

Neural stem cell(NSC)transplantation is a promising strategy for replacing lost neurons following spinal cord injury.However,the survival and differentiation of transplanted NSCs is limited,possibly owing to the neurotoxic inflammatory microenvironment.Because of the important role of glucose metabolism in M1/M2 polarization of microglia/macrophages,we hypothesized that altering the phenotype of microglia/macrophages by regulating the activity of aldose reductase(AR),a key enzyme in the polyol pathway of glucose metabolism,would provide a more beneficial microenvironment for NSC survival and differentiation.Here,we reveal that inhibition of host AR promoted the polarization of microglia/macrophages toward the M2 phenotype in lesioned spinal cord injuries.M2 macrophages promoted the differentiation of NSCs into neurons in vitro.Transplantation of NSCs into injured spinal cords either deficient in AR or treated with the AR inhibitor sorbinil promoted the survival and neuronal differentiation of NSCs at the injured spinal cord site and contributed to locomotor functional recovery.Our findings suggest that inhibition of host AR activity is beneficial in enhancing the survival and neuronal differentiation of transplanted NSCs and shows potential as a treatment of spinal cord injury.     

Hypoxia‐induced polypoid giant cancer cells in glioma promote the transformation of tumor‐associated macrophages to a tumor‐supportive phenotype

AimsPolypoid giant cancer cells (PGCCs) represent a unique subgroup of stem‐like cells, acting as a critical factor in promoting the recurrence of various solid tumors. The effect of PGCCs on the tumor malignancy of glioma and its immune microenvironment remains unclear.MethodsBioinformatic analysis was performed to investigate the relationship between M2 tumor‐associated macrophages (TAMs) infiltration and survival of glioblastoma (GBM) patients. The spatial location of M2 TAMs in GBM was also investigated using the Ivy Glioblastoma Atlas Project (Ivy GAP) database. PGCCs were quantified in glioma of different grades. CoCl₂ was used to induce PGCCs in cultures of A172 cells. PGCCs, and their progeny cells in cultures were further evaluated for morphological features, tumorsphere formation, and TAMs activation.ResultsThe magnitude of M2 TAMs infiltration is significantly correlated with poor survival in GBM patients. M2 TAMs were enriched in the perinecrotic zone (PNZ) of GBM and positively correlated with hypoxic levels. Increased PGCCs were detected in glioma specimens of higher grades. CoCl₂ induced hypoxia and the transformation of A172 cultures into PGCCs, producing the progeny cells, PGCCs‐Dau, through asymmetric division. PGCCs and PGCCs‐Dau possessed tumor stem cell‐like features, while PGCCs‐Dau enhanced the polarization of TAMs into an M2 phenotype with relevance to immunosuppression and malignancy in GBM.ConclusionsPGCCs promote malignancy and immune‐suppressive microenvironment in GBM. PGCCs or their progeny cells may be a potential therapeutic target for GBM.     

Adoptive transfer of M2 macrophages promotes locomotor recovery in adult rats after spinal cord injury

Classically activated pro-inflammatory (M1) and alternatively activated anti-inflammatory (M2) macrophages populate the local microenvironment after spinal cord injury (SCI). The former type is neurotoxic while the latter has positive effects on neuroregeneration and is less toxic. In addition, while the M1 macrophage response is rapidly induced and sustained, M2 induction is transient. A promising strategy for the repair of SCI is to increase the fraction of M2 cells and prolong their residence time. This study investigated the effect of M2 macrophages induced from bone marrow-derived macrophages on the local microenvironment and their possible role in neuroprotection after SCI. M2 macrophages produced anti-inflammatory cytokines such as interleukin (IL)-10 and transforming growth factor β and infiltrated into the injured spinal cord, stimulated M2 and helper T (Th)2 cells, and produced high levels of IL-10 and -13 at the site of injury. M2 cell transfer decreased spinal cord lesion volume and resulted in increased myelination of axons and preservation of neurons. This was accompanied by significant locomotor improvement as revealed by Basso, Beattie and Bresnahan locomotor rating scale, grid walk and footprint analyses. These results indicate that M2 adoptive transfer has beneficial effects for the injured spinal cord, in which the increased number of M2 macrophages causes a shift in the immunological response from Th1- to Th2-dominated through the production of anti-inflammatory cytokines, which in turn induces the polarization of local microglia and/or macrophages to the M2 subtype, and creates a local microenvironment that is conducive to the rescue of residual myelin and neurons and preservation of neuronal function.     

Microglial/Macrophage polarization and function in brain injury and repair after stroke

Stroke is a leading cause of disability and mortality, with limited treatment options. After stroke injury, microglia and CNS-resident macrophages are rapidly activated and regulate neuropathological processes to steer the course of functional recovery. To accelerate this recovery, microglia can engulf dying cells and clear irreparably-damaged tissues, thereby creating a microenvironment that is more suitable for the formation of new neural circuitry. In addition, monocyte-derived macrophages cross the compromised blood-brain barrier to infiltrate the injured brain. The specific functions of myeloid lineage cells in brain injury and repair are diverse and dependent on phenotypic polarization statuses. However, it remains to be determined to what degree the CNS-invading macrophages occupy different functional niches from CNS-resident microglia. In this review, we describe the physiological characteristics and functions of microglia in the developing and adult brain. We also review (a) the activation and phenotypic polarization of microglia and macrophages after stroke, (b) molecular mechanisms that control polarization status, and (c) the contribution of microglia to brain pathology versus repair. Finally, we summarize current breakthroughs in therapeutic strategies that calibrate microglia/macrophage responses after stroke.     

CCL5, CCR1 and CCR5 in murine glioblastoma: immune cell infiltration and survival rates are not dependent on individual expression of either CCR1 or CCR5

Glioblastoma multiforme (GBM) is the most malignant brain tumor. Microglia/macrophages are found within human GBM where they likely promote tumor progression. We report that CCL5, CCR1, and CCR5 are expressed in glioblastoma. Individual deletion of CCR1 or CCR5 had little to no effect on survival of tumor bearing mice, or numbers of glioblastoma-infiltrated microglia/macrophages or lymphocytes. CCL5 promoted in vitro migration of wild type, CCR1- or CCR5-deficient microglia/macrophages that was blocked by the dual CCR1/CCR5 antagonist, Met-CCL5. These data suggest that CCL5 functions within the glioblastoma microenvironment through CCR1 and CCR5 in a redundant manner.     

Neuronal extracellular microRNAs miR-124 and miR-9 mediate cell–cell communication between neurons and microglia

In contrast to peripheral macrophages, microglia in the central nervous system (CNS) exhibit a specific deactivated phenotype; however, it is not clear how this phenotype is maintained. Two alternative hypotheses were postulated recently: (a) microglia differ from peripheral macrophages being derived from the yolk sac (YS), whereas peripheral macrophages originate from bone marrow (BM); (b) microglia acquire a specific phenotype under the influence of the CNS microenvironment. We have previously shown that microglia express miR-124, which was also induced in BM-derived macrophages co-cultured with a neurons. We here investigated the possibility of horizontal transfer of the neuron-specific microRNAs miR-124 and miR-9 from primary neurons to microglia/macrophages. We found that after incubation with neuronal conditioned media (NCM), macrophages downregulated activation markers MHC class II and CD45. Neither cultured adult microglia nor YS- and BM-derived macrophages demonstrated intrinsic levels of miR-124 expression. However, after incubation with NCM, miR-124 was induced in both YS- and BM-derived macrophages. Biochemical analysis demonstrated that the NCM contained miR-124 and miR-9 in complex with small proteins, large high-density lipoproteins (HDLs), and exosomes. MiR-124 and miR-9 were promptly released from neurons, and this process was inhibited by tetrodotoxin, indicating an important role of neuronal electric activity in secretion of these microRNAs. Incubation of macrophages with exogenous miR-124 resulted in efficient translocation of miR-124 into the cytoplasm. This study demonstrates an important role of neuronal miRNAs in communication of neurons with microglia, which favors the hypothesis that microglia acquire a specific phenotype under the influence of the CNS microenvironment.