Table 3.

Key advances in hPSC-EC differentiation.

Initial cell type	Bioactive factors	Culture	Key advances	Refs
hESC	Spontaneous differentiation in medium without LIF and bFGF; Purified PECAM1+ cells.	EB	Isolated PECAM1+ cells display characteristics like vessel endothelium in vitro or in vivo.	2002, Levenberg et al. [52]
hESC	FBS	EB	Role of SDF-1 and CXCR4 in initial vessel formation.	2007, Chen et al. [53]
hESC	FBS	monolayer	A scalable two-dimensional method avoiding an embryoid-body intermediate.	2007, Wang et al. [55]
hESC	BMP-4, VEGF, bFGF	monolayer	Role of BMP-4, VEGF and bFGF in hemangioblast differentiation.	2008, Lu et al. [56]
hESC	VEGF, bFGF	EB	An extracellular matrix culture system for xeno-free hESC-ECs.	2009, Li et al. [61]
hESC	TGFβ inhibitor, BMP-4, Activin A, FGF-2, VEGF-A	EB	Role of TGFβ inhibition and Id1 for endothelial cell commitment.	2010, James et al. [57,58]
iPSC	microRNA-21, TGFβ-2, VEGF	monolayer	MicroRNA-21 and TGF-β2 signaling pathways regulate iPSC differentiation to endothelial lineage.	2014, Bernardini et al. [59]
hESC, iPSC	CHIR99021	monolayer	Role of WNT/β-catenin in generating endothelial progenitors.	2014, Lian et al. [60]
hESC, iPSC	BMP4, Activin A, CHIR99021, VEGF, SB431542	monolayer	Described efficient generation of ECs and pericytes from hPSCs under defined conditions and two assays for functional hPSC-EC evaluation.	2014, Orlova et al. [64]
hESC, iPSC	BMP-4, VEGF-A	monolayer	Produced mature ECs with 80% efficiency in six days and purification to 99% via surface markers.	2015, Patsch et al. [65]
hESC, iPSC	Activin A, BMP4, CHIR99021, VEGF, bFGF	monolayer	First protocol that provides a common platform for directed differentiation of cardiomyocytes and endothelial subtypes from hPSCs, with >90% EC efficiency.	2016, Palpant et al. [63]
hESC, iPSC	FGF, VEGF, BMP, SB431542	monolayer	Identified pathways for regulating arterial EC differentiation via single-cell RNAseq and derived hPSC-arterial EC that improved cardiovascular function.	2017, Zhang et al. [66]