Human brain microvascular endothelial cell pairs model tissue-level blood–brain barrier function
| Autor: | Jorge A Jimenez, Kevin Kit Parker, Blakely B. O'Connor, Philip Demokritou, Dimitrios Bitounis, Herdeline Ann M. Ardoña, John F. Zimmerman, Thomas Grevesse |
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| Rok vydání: | 2020 |
| Předmět: |
Cytoplasm
Stress fiber Endothelium Biophysics 02 engineering and technology Blood–brain barrier Biochemistry Cell junction Permeability Capillary Permeability 03 medical and health sciences medicine Humans Dimethylpolysiloxanes Cytoskeleton Cells Cultured Barrier function 030304 developmental biology Cell Nucleus 0303 health sciences Chemistry Microcirculation Brain Endothelial Cells Biological Transport Human brain 021001 nanoscience & nanotechnology Actins Endothelial stem cell Intercellular Junctions medicine.anatomical_structure Blood-Brain Barrier Cerebrovascular Circulation Nanoparticles Original Article 0210 nano-technology |
| Zdroj: | Integr Biol (Camb) |
| ISSN: | 1757-9708 |
| Popis: | The blood–brain barrier plays a critical role in delivering oxygen and nutrients to the brain while preventing the transport of neurotoxins. Predicting the ability of potential therapeutics and neurotoxicants to modulate brain barrier function remains a challenge due to limited spatial resolution and geometric constraints offered by existing in vitro models. Using soft lithography to control the shape of microvascular tissues, we predicted blood–brain barrier permeability states based on structural changes in human brain endothelial cells. We quantified morphological differences in nuclear, junction, and cytoskeletal proteins that influence, or indicate, barrier permeability. We established a correlation between brain endothelial cell pair structure and permeability by treating cell pairs and tissues with known cytoskeleton-modulating agents, including a Rho activator, a Rho inhibitor, and a cyclic adenosine monophosphate analog. Using this approach, we found that high-permeability cell pairs showed nuclear elongation, loss of junction proteins, and increased actin stress fiber formation, which were indicative of increased contractility. We measured traction forces generated by high- and low-permeability pairs, finding that higher stress at the intercellular junction contributes to barrier leakiness. We further tested the applicability of this platform to predict modulations in brain endothelial permeability by exposing cell pairs to engineered nanomaterials, including gold, silver–silica, and cerium oxide nanoparticles, thereby uncovering new insights into the mechanism of nanoparticle-mediated barrier disruption. Overall, we confirm the utility of this platform to assess the multiscale impact of pharmacological agents or environmental toxicants on blood–brain barrier integrity. |
| Databáze: | OpenAIRE |
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