Endothelial response to blood-brain barrier disruption in the human brain
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.
Authors
- Cristal Gomez
- Christina Amidei (ORCID: https://orcid.org/0000-0003-4558-8664)
- Guillaume Bouchoux (ORCID: https://orcid.org/0000-0002-2444-025X)
- Daniel Y. Zhang (ORCID: https://orcid.org/0000-0001-9962-9295)
- Mark W. Youngblood (ORCID: https://orcid.org/0000-0002-1044-8015)
- Farida Korobova
- Víctor A. Arrieta (ORCID: https://orcid.org/0000-0003-2738-9741)
- Brandyn Castro (ORCID: https://orcid.org/0000-0003-3412-9761)
- Rachel Ward
- Crismita Dmello (ORCID: https://orcid.org/0000-0002-1688-9663)
- Roger Stupp (ORCID: https://orcid.org/0000-0002-5483-3118)
- John F. Bebawy (ORCID: https://orcid.org/0000-0003-4441-3213)
- Andrew Gould (ORCID: https://orcid.org/0009-0000-9543-8125)
- Adam M. Sonabend (ORCID: https://orcid.org/0000-0002-8347-1945)
- M. Luisa Iruela‐Arispe (ORCID: https://orcid.org/0000-0002-3050-4168)
- Karl J. Habashy (ORCID: https://orcid.org/0000-0003-1210-378X)
- Michael Canney (ORCID: https://orcid.org/0000-0003-3945-3560)
- Ye Hou (ORCID: https://orcid.org/0000-0001-9079-573X)
- Li Chen (ORCID: https://orcid.org/0000-0001-5345-1620)
- Yue Feng (ORCID: https://orcid.org/0000-0001-7741-8534)
- Yu Luan
Institutions
- Northwestern University (US)
- Rush University Medical Center (US)
- Inner Mongolia University (CN)
- University of Chicago (US)
- Northwestern Medicine (US)
- Neurological Surgery (US)
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Publication Details
- Journal
- JCI Insight
- Published
- 2024-12-26
- DOI
- https://doi.org/10.1172/jci.insight.187328
- Citations
- 5
- Primary Topic
- Photoacoustic and Ultrasonic Imaging
- Type
- article
- Field-Weighted Citation Impact
- 0.92
Funders
- Northwestern University
- National Institutes of Health
- Robert H. Lurie Comprehensive Cancer Center
- National Cancer Institute