Tissue-engineered blood-brain barrier models via directed differentiation of human induced pluripotent stem cells.
Gabrielle N GrifnoAlanna M FarrellRaleigh M LinvilleDiego ArevaloJoo Ho KimLuo GuPeter C SearsonPublished in: Scientific reports (2019)
Three-dimensional (3D) tissue-engineered models of the blood-brain barrier (BBB) recapitulate in vivo shear stress, cylindrical geometry, and cell-ECM interactions. Here we address four issues associated with BBB models: cell source, barrier function, cryopreservation, and matrix stiffness. We reproduce a directed differentiation of brain microvascular endothelial cells (dhBMECs) from two fluorescently labeled human induced pluripotent stem cell lines (hiPSCs) and demonstrate physiological permeability of Lucifer yellow over six days. Microvessels formed from cryopreserved dhBMECs show expression of BBB markers and maintain physiological barrier function comparable to non-cryopreserved cells. Microvessels displaying physiological barrier function are formed in collagen I hydrogels with stiffness matching that of human brain. The dilation response of microvessels was linear with increasing transmural pressure and was dependent on matrix stiffness. Together these results advance capabilities for tissue-engineered BBB models.
Keyphrases
- blood brain barrier
- endothelial cells
- induced pluripotent stem cells
- high glucose
- cerebral ischemia
- single cell
- poor prognosis
- cell therapy
- induced apoptosis
- vascular endothelial growth factor
- stem cells
- wound healing
- pet imaging
- bone marrow
- multiple sclerosis
- binding protein
- cell cycle arrest
- resting state
- drug induced
- functional connectivity