Gould Andrew, Luan Yu, Hou Ye, Korobova Farida V, Chen Li, Arrieta Victor A, Amidei Christina, Ward Rachel, Gomez Cristal, Castro Brandyn, Habashy Karl, Zhang Daniel, Youngblood Mark, Dmello Crismita, Bebawy John, Bouchoux Guillaume, Stupp Roger, Canney Michael, Yue Feng, Iruela-Arispe M Luisa, Sonabend Adam M
Department of Neurological Surgery.
Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, and.
JCI Insight. 2024 Dec 26;10(4):e187328. doi: 10.1172/jci.insight.187328.
Cerebral endothelial cell (EC) injury and blood-brain barrier (BBB) permeability contribute to neuronal injury in acute neurological disease states. Preclinical experiments have used animal models to study this phenomenon, yet the response of human cerebral ECs to BBB disruption remains unclear. In our phase I clinical trial (ClinicalTrials.gov NCT04528680), we used low-intensity pulsed ultrasound with microbubbles (LIPU/MB) to induce transient BBB disruption of peritumoral brain in patients with recurrent glioblastoma. We found radiographic evidence that BBB integrity was mostly restored within 1 hour of this procedure. Using single-cell RNA sequencing and transmission electron microscopy, we analyzed the acute response of human brain ECs to ultrasound-mediated BBB disruption. Our analysis revealed distinct EC gene expression changes after LIPU/MB, particularly in genes related to neurovascular barrier function and structure, including changes to genes involved in the basement membrane, EC cytoskeleton, and junction complexes, as well as caveolar transcytosis and various solute transporters. Ultrastructural analysis showed that LIPU/MB led to a decrease in luminal caveolae, the emergence of cytoplasmic vacuoles, and the disruption of the basement membrane and tight junctions, among other things. These findings suggested that acute BBB disruption by LIPU/MB led to specific transcriptional and ultrastructural changes and could represent a conserved mechanism of BBB repair after neurovascular injury in humans.
脑内皮细胞（EC）损伤和血脑屏障（BBB）通透性增加在急性神经疾病状态下会导致神经元损伤。临床前实验已使用动物模型来研究这一现象，但人类脑内皮细胞对血脑屏障破坏的反应仍不清楚。在我们的I期临床试验（ClinicalTrials.gov NCT04528680）中，我们使用低强度脉冲超声联合微泡（LIPU/MB）诱导复发性胶质母细胞瘤患者瘤周脑组织的血脑屏障短暂破坏。我们发现影像学证据表明，在此操作后1小时内血脑屏障完整性大多得以恢复。利用单细胞RNA测序和透射电子显微镜，我们分析了人类脑内皮细胞对超声介导的血脑屏障破坏的急性反应。我们的分析揭示了LIPU/MB后内皮细胞基因表达的明显变化，特别是与神经血管屏障功能和结构相关的基因，包括与基底膜、内皮细胞细胞骨架和连接复合体相关的基因变化，以及小窝转胞吞作用和各种溶质转运体的变化。超微结构分析表明，LIPU/MB导致管腔小窝减少、细胞质空泡出现、基底膜和紧密连接破坏等。这些发现表明，LIPU/MB引起的急性血脑屏障破坏导致了特定的转录和超微结构变化，可能代表了人类神经血管损伤后血脑屏障修复的一种保守机制。
