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Resource and Technical AdvanceIn-Press PreviewNeuroscienceVascular biology Open Access | 10.1172/jci.insight.187328

Endothelial Response to Blood-Brain Barrier Disruption in the Human Brain

Andrew Gould,1 Yu Luan,2 Ye Hou,3 Farida V. Korobova,4 Li Chen,1 Victor A. Arrieta,1 Christina Amidei,1 Rachel Ward,1 Cristal Gomez,1 Brandyn Castro,1 Karl Habashy,1 Daniel Zhang,1 Mark Youngblood,1 Crismita Dmello,1 John Bebawy,1 Guillaume Bouchoux,5 Roger Stupp,1 Michael Canney,5 Feng Yue,6 M. Luisa Iruela-Arispe,4 and Adam M. Sonabend1

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Gould, A. in: JCI | PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Luan, Y. in: JCI | PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Hou, Y. in: JCI | PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Korobova, F. in: JCI | PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Chen, L. in: JCI | PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Arrieta, V. in: JCI | PubMed | Google Scholar |

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Amidei, C. in: JCI | PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Ward, R. in: JCI | PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Gomez, C. in: JCI | PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Castro, B. in: JCI | PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Habashy, K. in: JCI | PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Zhang, D. in: JCI | PubMed | Google Scholar |

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Youngblood, M. in: JCI | PubMed | Google Scholar |

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Dmello, C. in: JCI | PubMed | Google Scholar |

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Bebawy, J. in: JCI | PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Bouchoux, G. in: JCI | PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Stupp, R. in: JCI | PubMed | Google Scholar |

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Canney, M. in: JCI | PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Yue, F. in: JCI | PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Iruela-Arispe, M. in: JCI | PubMed | Google Scholar |

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Institute of Biomedicine, College of Life Sciences, Inner Mongolia University, Hohhot, China

4Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

5Carthera, Lyon, France

6Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehens, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Sonabend, A. in: JCI | PubMed | Google Scholar

Published December 26, 2024 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.187328.
Copyright © 2024, Gould et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 26, 2024 - Version history
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Abstract

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 1 clinical trial (NCT04528680), we used low-intensity pulsed ultrasound with microbubbles (LIPU/MB) to induce transient BBB disruption of peri-tumoral 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.

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  • Version 1 (December 26, 2024): In-Press Preview
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