Generation of hiPSC-derived brain microvascular endothelial cells using a combination of directed differentiation and transcriptional reprogramming strategies.
Aomeng CuiRonak PatelPatrick BoscoUgur AkcanEmily RichtersPaula Barrilero DelgadoDritan AgalliuAndrew A SproulPublished in: bioRxiv : the preprint server for biology (2024)
The blood-brain barrier (BBB), formed by specialized brain microvascular endothelial cells (BMECs), regulates brain function in health and disease. In vitro modeling of the human BBB is limited by the lack of robust hiPSC protocols to generate BMECs. Here, we report generation, transcriptomic and functional characterization of reprogrammed BMECs (rBMECs) by combining hiPSC differentiation into BBB-primed endothelial cells and reprogramming with two BBB transcription factors FOXF2 and ZIC3. rBMECs express a subset of the BBB gene repertoire including tight junctions and transporters, exhibit stronger paracellular barrier properties, lower caveolar-mediated transcytosis, and similar p-Glycoprotein activity compared to primary HBMECs. They can acquire an inflammatory phenotype when treated with oligomeric Aβ42. rBMECs integrate with hiPSC-derived pericytes and astrocytes to form a 3D neurovascular system using the MIMETAS microfluidics platform. This novel 3D system resembles the in vivo BBB at structural and functional levels to enable investigation of pathogenic mechanisms of neurological diseases.
Keyphrases
- blood brain barrier
- endothelial cells
- cerebral ischemia
- high glucose
- white matter
- transcription factor
- resting state
- vascular endothelial growth factor
- healthcare
- public health
- gene expression
- genome wide
- mental health
- palliative care
- oxidative stress
- high throughput
- single cell
- dna methylation
- brain injury
- copy number
- subarachnoid hemorrhage
- newly diagnosed
- rna seq
- genome wide identification
- heat shock protein