为脑室下区的胶质母细胞瘤细胞开发基于脑室内腺相关病毒的标记策略。

IF 3.7 Q1 CLINICAL NEUROLOGY Neuro-oncology advances Pub Date : 2024-09-28 eCollection Date: 2024-01-01 DOI:10.1093/noajnl/vdae161
Arnaud Lombard, Damla Isci, Gilles Reuter, Emmanuel Di Valentin, Alexandre Hego, Didier Martin, Bernard Rogister, Virginie Neirinckx
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引用次数: 0

摘要

背景:胶质母细胞瘤(GBM)是一种可怕的脑肿瘤:胶质母细胞瘤(GBM)是一种可怕的脑肿瘤,它与成人脑室下区(SVZ)有特殊关系,被认为与疾病的发生、发展和复发有关:我们提出了一种基于脑室内(icv)重组腺相关病毒(AAV)介导的颜色转换方法来检测和追踪位于脑室下区的异种移植 GBM 细胞的新策略。我们使用了不同患者来源的 GBM 干样细胞(GSCs),首先用逆转录病毒载体(LRLG)转导这些细胞,该载体包含 eGFP 基因上游的 lox-dsRed-STOP-lox 盒,然后用表达 Cre 重配酶的 rAAVs 转导这些细胞。使用流式细胞仪和荧光显微镜对体外和体内的红绿荧光进行分析:结果:在比较了不同 rAAV 血清型的效率后,我们证实用 rAAV-Cre 体外转导 GSC-LRLG 会诱导荧光从红色转为绿色。同时,我们还验证了 rAAV 转导仅限于侧脑室壁。因此,我们将这种转化方法应用于 2 个源自患者的正位 GSC 异种移植模型,结果表明,在 GSC-LRLG 肿瘤植入后,icv 注射 rAAV-DJ-Cre 会引发脑室周围区域的红色 GSCs 转化为绿色。绿色GSCs也出现在远处,包括迁移束和肿瘤核心:本研究不仅揭示了SVZ嵌顿GBM细胞的可能结果,还表明icv注射rAAV载体可转导并潜在调节脑室周围区域难以到达的GBM细胞的基因表达。
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Development of an intraventricular adeno-associated virus-based labeling strategy for glioblastoma cells nested in the subventricular zone.

Background: Glioblastoma (GBM) is a dreadful brain tumor, with a particular relationship to the adult subventricular zone (SVZ) that has been described as relevant to disease initiation, progression, and recurrence.

Methods: We propose a novel strategy for the detection and tracking of xenografted GBM cells that are located in the SVZ, based on an intracerebroventricular (icv) recombinant adeno-associated virus (AAV)-mediated color conversion method. We used different patient-derived GBM stem-like cells (GSCs), which we transduced first with a retroviral vector (LRLG) that included a lox-dsRed-STOP-lox cassette, upstream of the eGFP gene, then with rAAVs expressing the Cre-recombinase. Red and green fluorescence is analyzed in vitro and in vivo using flow cytometry and fluorescence microscopy.

Results: After comparing the efficiency of diverse rAAV serotypes, we confirmed that the in vitro transduction of GSC-LRLG with rAAV-Cre induced a switch from red to green fluorescence. In parallel, we verified that rAAV transduction was confined to the walls of the lateral ventricles. We, therefore, applied this conversion approach in 2 patient-derived orthotopic GSC xenograft models and showed that the icv injection of an rAAV-DJ-Cre after GSC-LRLG tumor implantation triggered the conversion of red GSCs to green, in the periventricular region. Green GSCs were also found at distant places, including the migratory tract and the tumor core.

Conclusions: This study not only sheds light on the putative outcome of SVZ-nested GBM cells but also shows that icv injection of rAAV vectors allows to transduce and potentially modulate gene expression in hard-to-reach GBM cells of the periventricular area.

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