Investigating Blood-Brain Barrier Dysfunction in Schizophrenia Using Brain Microvascular Endothelial Cells Derived from Patient-Specific Stem Cells

Sovannarath Pong, MS

Beth Israel Deaconess Medical Center
Investigating Blood-Brain Barrier Dysfunction in Schizophrenia Using Brain Microvascular Endothelial Cells Derived from Patient-Specific Stem Cells

Scientific Abstract

Background: Blood-brain barrier (BBB) disruption is known to play a role in schizophrenia (SZ) and bipolar disorder (BD). Brain microvascular endothelial cells (BMECs) make up the BBB, but little is known regarding their role in BBB disruption in SZ and BD. We hypothesized that BMEC function is altered in SZ and BD.

Methods: Fibroblasts from SZ, BD and healthy control (HC) subjects (n=4 per group) were reprogrammed into induced pluripotent stem cells (iPSCs). We adapted a protocol to generate iPSC-derived BMECs. To evaluate barrier function we measured transendothelial electrical resistance (TEER) using STX2 chopstick electrodes and EVOM2 voltohmeter. RT-qPCR was performed to measure mRNA expressions of BMEC specific markers (CLDN5, TJP1, OCLN, SLC2A1, PECAM1) and several genes previously implicated in SZ (CAV1, CDH5, ICAM1, ABCB1, HSPG2, FN1, LRP1). Western blot analysis was performed to measure protein levels of tight junction proteins (CLDN5, TJP1, and OCLN).

Results: TEER was significantly different between HC and SZ (Cohen’s d= 1.3, h2= 0.21, P=0.009), but no difference between HC and BD or BD and SZ. Gene expression for CLDN5, SLC2A1, PECAM1, FN1, and HSPG2 were significantly downregulated in iPSC-derived BMECs from both SZ and BD groups (p<0.05) when compared to HCs. CAV1 and LRP1 were also downregulated in SZ (p<0.05) but not BD group, whereas ICAM1 was significantly upregulated in SZ (P<0.05) but not in BD. Tight junction protein levels for CLDN5 and OCLN were lower in iPSC-derived BMECs from the SZ group compared to HCs, but not for the BD group.

Conclusions: To the best of our knowledge, this is the first study to date to identify a structural BBB deficit in SZ, as well as reduction in gene expression and protein levels related to tight junction formation. This suggests there may be innate disease-specific deficits in BMECs in schizophrenia that result in BBB dysfunction.

Live Zoom Session – April 21st

research Areas

Authors

Sovannarath Pong, MS, Paulo Lizano, MD, PhD, Rakesh Karmacharya, MD, PhD

Principal Investigator

Rakesh Karmacharya, MD, PhD

Affiliated Website