Oxygen-Glucose Deprivation/Reoxygenation-Induced Barrier Disruption at the Human Blood-Brain Barrier is Partially Mediated Through the HIF-1 Pathway.
Shyanne PageSnehal RautAbraham Jacob Al-AhmadPublished in: Neuromolecular medicine (2019)
The blood-brain barrier (BBB) plays an important role in brain homeostasis. Hypoxia/ischemia constitutes an important stress factor involved in several neurological disorders by inducing the disruption of the BBB, ultimately leading to cerebral edema formation. Yet, our current understanding of the cellular and molecular mechanisms underlying the BBB disruption following cerebral hypoxia/ischemia remains limited. Stem cell-based models of the human BBB present some potentials to address such issues. Yet, such models have not been validated in regard of its ability to respond to hypoxia/ischemia as existing models. In this study, we investigated the cellular response of two iPSC-derived brain microvascular endothelial cell (BMEC) monolayers to respond to oxygen-glucose deprivation (OGD) stress, using two induced pluripotent stem cells (iPSC) lines. iPSC-derived BMECs responded to prolonged (24 h) and acute (6 h) OGD by showing a decrease in the barrier function and a decrease in tight junction complexes. Such iPSC-derived BMECs responded to OGD stress via a partial activation of the HIF-1 pathway, whereas treatment with anti-angiogenic pharmacological inhibitors (sorafenib, sunitinib) during reoxygenation worsened the barrier function. Taken together, our results suggest such models can respond to hypoxia/ischemia similarly to existing in vitro models and support the possible use of this model as a screening platform for identifying novel drug candidates capable to restore the barrier function following hypoxic/ischemic injury.
Keyphrases
- blood brain barrier
- induced pluripotent stem cells
- endothelial cells
- cerebral ischemia
- high glucose
- stem cells
- resting state
- type diabetes
- subarachnoid hemorrhage
- drug induced
- stress induced
- functional connectivity
- blood pressure
- skeletal muscle
- liver failure
- white matter
- emergency department
- metabolic syndrome
- oxidative stress
- respiratory failure
- blood glucose
- pluripotent stem cells
- acute respiratory distress syndrome
- single cell
- intensive care unit
- diabetic rats
- brain injury