Programming brain endothelial identity: Transcription factor and genome engineering approaches to improve iPSC-derived BBB models

Human induced pluripotent stem cell-derived brain endothelial-like cells (iBECs) serve as important human relevant in vitro blood-brain barrier (BBB) models for evaluating central nervous system (CNS)-targeted therapies. However, conventional differentiation protocols often generate heterogeneous populations constrained by incomplete endothelial maturation. Overcoming these limitations requires precise control over developmental gene regulatory networks throughout differentiation. This review examines transcription factor-based forward reprogramming strategies designed to induce brain endothelial cell fate and prime BBB identity. Integrating these approaches with novel genome engineering tools enables the rational design of next generation BBB models with improved physiological fidelity and predictive power for CNS therapeutic discovery and validation.