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Development of a human in vitro blood–brain tumor barrier model of diffuse intrinsic pontine glioma to better understand the chemoresistance
Fluids and Barriers of the CNS ( IF 5.9 ) Pub Date : 2020-06-02 , DOI: 10.1186/s12987-020-00198-0
Clémence Deligne 1 , Johan Hachani 2 , Sophie Duban-Deweer 2 , Samuel Meignan 3, 4, 5 , Pierre Leblond 6 , Angel M Carcaboso 7 , Yasuteru Sano 8 , Fumitaka Shimizu 8 , Takashi Kanda 8 , Fabien Gosselet 1 , Marie-Pierre Dehouck 1 , Caroline Mysiorek 1
Affiliation  

Background Pediatric diffuse intrinsic pontine glioma (DIPG) represents one of the most devastating and lethal brain tumors in children with a median survival of 12 months. The high mortality rate can be explained by the ineligibility of patients to surgical resection due to the diffuse growth pattern and midline localization of the tumor. While the therapeutic strategies are unfortunately palliative, the blood–brain barrier (BBB) is suspected to be responsible for the treatment inefficiency. Located at the brain capillary endothelial cells (ECs), the BBB has specific properties to tightly control and restrict the access of molecules to the brain parenchyma including chemotherapeutic compounds. However, these BBB specific properties can be modified in a pathological environment, thus modulating brain exposure to therapeutic drugs. Hence, this study aimed at developing a syngeneic human blood–brain tumor barrier model to understand how the presence of DIPG impacts the structure and function of brain capillary ECs. Methods A human syngeneic in vitro BBB model consisting of a triple culture of human (ECs) (differentiated from CD34 + -stem cells), pericytes and astrocytes was developed. Once validated in terms of BBB phenotype, this model was adapted to develop a blood–brain tumor barrier (BBTB) model specific to pediatric DIPG by replacing the astrocytes by DIPG-007, -013 and -014 cells. The physical and metabolic properties of the BBTB ECs were analyzed and compared to the BBB ECs. The permeability of both models to chemotherapeutic compounds was evaluated. Results In line with clinical observation, the integrity of the BBTB ECs remained intact until 7 days of incubation. Both transcriptional expression and activity of efflux transporters were not strongly modified by the presence of DIPG. The permeability of ECs to the chemotherapeutic drugs temozolomide and panobinostat was not affected by the DIPG environment. Conclusions This original human BBTB model allows a better understanding of the influence of DIPG on the BBTB ECs phenotype. Our data reveal that the chemoresistance described for DIPG does not come from the development of a “super BBB”. These results, validated by the absence of modification of drug transport through the BBTB ECs, point out the importance of understanding the implication of the different protagonists in the pathology to have a chance to significantly improve treatment efficiency.

中文翻译:

弥漫性内源性脑桥胶质瘤人体外血脑肿瘤屏障模型的开发以更好地了解化学耐药性

背景 小儿弥漫性内源性脑桥胶质瘤 (DIPG) 是儿童中最具破坏性和致命性的脑肿瘤之一,中位生存期为 12 个月。高死亡率可以解释为由于肿瘤的弥漫性生长模式和中线定位,患者不适合手术切除。虽然不幸的是治疗策略是姑息性的,但血脑屏障 (BBB) 被怀疑是导致治疗效率低下的原因。BBB 位于脑毛细血管内皮细胞 (EC) 处,具有严格控制和限制分子进入包括化疗化合物在内的脑实质的特定特性。然而,这些 BBB 特定特性可以在病理环境中进行修改,从而调节大脑对治疗药物的暴露。因此,本研究旨在开发一种同源的人类血脑肿瘤屏障模型,以了解 DIPG 的存在如何影响脑毛细血管内皮细胞的结构和功能。方法 开发了由人类 (EC)(从 CD34 + -干细胞分化而来)、周细胞和星形胶质细胞的三重培养物组成的人类同基因体外 BBB 模型。一旦在 BBB 表型方面得到验证,该模型就适用于通过用 DIPG-007、-013 和 -014 细胞替换星形胶质细胞来开发特定于小儿 DIPG 的血脑肿瘤屏障 (BBTB) 模型。分析了 BBTB ECs 的物理和代谢特性,并将其与 BBB ECs 进行了比较。评估了两种模型对化疗化合物的渗透性。结果与临床观察一致,BBTB ECs 的完整性在孵育 7 天之前保持完整。外排转运蛋白的转录表达和活性均未因 DIPG 的存在而受到强烈改变。ECs 对化疗药物替莫唑胺和帕比司他的渗透性不受 DIPG 环境的影响。结论 这种原始的人类 BBTB 模型可以更好地了解 DIPG 对 BBTB ECs 表型的影响。我们的数据显示,DIPG 所描述的化学抗性并非来自“超级 BBB”的发展。这些结果通过 BBTB ECs 的药物转运没有改变而得到验证,指出了解病理学中不同主角的含义对于有机会显着提高治疗效率的重要性。ECs 对化疗药物替莫唑胺和帕比司他的渗透性不受 DIPG 环境的影响。结论 这种原始的人类 BBTB 模型可以更好地了解 DIPG 对 BBTB ECs 表型的影响。我们的数据显示,DIPG 所描述的化学抗性并非来自“超级 BBB”的发展。这些结果通过 BBTB ECs 的药物转运没有改变而得到验证,指出了解病理学中不同主角的含义对于有机会显着提高治疗效率的重要性。ECs 对化疗药物替莫唑胺和帕比司他的渗透性不受 DIPG 环境的影响。结论 这种原始的人类 BBTB 模型可以更好地了解 DIPG 对 BBTB ECs 表型的影响。我们的数据显示,DIPG 所描述的化学抗性并非来自“超级 BBB”的发展。这些结果通过 BBTB ECs 的药物转运没有改变而得到验证,指出了解病理学中不同主角的含义对于有机会显着提高治疗效率的重要性。结论 这种原始的人类 BBTB 模型可以更好地了解 DIPG 对 BBTB ECs 表型的影响。我们的数据显示,DIPG 所描述的化学抗性并非来自“超级 BBB”的发展。这些结果通过 BBTB ECs 的药物转运没有改变而得到验证,指出了解病理学中不同主角的含义对于有机会显着提高治疗效率的重要性。结论 这种原始的人类 BBTB 模型可以更好地了解 DIPG 对 BBTB ECs 表型的影响。我们的数据显示,DIPG 所描述的化学抗性并非来自“超级 BBB”的发展。这些结果通过 BBTB ECs 的药物转运没有改变而得到验证,指出了解病理学中不同主角的含义对于有机会显着提高治疗效率的重要性。
更新日期:2020-06-02
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