Brain Pericytes and Wnt/β-Catenin Signaling Induce Functional Blood-Brain Barrier Phenotype in Human iPSC-Derived...

Area of Science:

• Neuroscience
• Cell Biology
• Biotechnology

Background:

• The blood-brain barrier (BBB) is crucial for brain health, regulating substance entry via tight junctions, transporters, and transcytosis.
• Existing in vitro BBB models fail to fully replicate the complex features of human brain microvascular endothelial cells (BMECs).
• BBB dysfunction is implicated in various cerebrovascular and neurodegenerative diseases.

Purpose of the Study:

• To develop an improved human in vitro model of the blood-brain barrier (BBB).
• To elucidate the synergistic mechanisms of pericyte-derived cues and Wnt/β-catenin signaling in BMEC differentiation.
• To establish a more accurate model for drug screening and disease modeling related to the BBB.

Main Methods:

• Generation of human induced pluripotent stem cell-derived endothelial cells (hiBMECs) through co-culture with isogenic brain pericytes.
• Activation of Wnt/β-catenin signaling to enhance BMEC differentiation and barrier function.
• Transcriptomic profiling to identify key gene networks and signaling pathways involved in BBB formation.

Main Results:

• The developed hiBMECs exhibited robust barrier properties, active efflux transporters, and appropriate inflammatory responses.
• Transcriptomic analysis revealed convergence on ETS1, SMAD3/4, and PPARγ transcriptional networks, creating a gene signature akin to the adult human BBB.
• Key pathways including sphingosine-1-phosphate, TGF-β, and angiopoietin/Tie2 were modulated by pericyte cues and Wnt signaling.

Conclusions:

• A synergistic mechanism involving brain pericytes and Wnt/β-catenin signaling drives human BMEC differentiation and BBB function.
• This study provides mechanistic insights into human BBB development.
• The novel hiPSC-derived BBB model offers enhanced functionality for future research, drug screening, and disease modeling.