Distinct families of multipotent heart progenitors play a central role in the 
generation of diverse cardiac, smooth muscle and endothelial cell lineages 
during mammalian cardiogenesis. The identification of precise paracrine signals 
that drive the cell-fate decision of these multipotent progenitors, and the 
development of novel approaches to deliver these signals in vivo, are critical 
steps towards unlocking their regenerative therapeutic potential. Herein, we 
have identified a family of human cardiac endothelial intermediates located in 
outflow tract of the early human fetal hearts (OFT-ECs), characterized by 
coexpression of Isl1 and CD144/vWF. By comparing angiocrine factors expressed by 
the human OFT-ECs and non-cardiac ECs, vascular endothelial growth factor 
(VEGF)-A was identified as the most abundantly expressed factor, and clonal 
assays documented its ability to drive endothelial specification of human 
embryonic stem cell (ESC)-derived Isl1+ progenitors in a VEGF receptor-dependent 
manner. Human Isl1-ECs (endothelial cells differentiated from hESC-derived ISL1+ 
progenitors) resemble OFT-ECs in terms of expression of the cardiac endothelial 
progenitor- and endocardial cell-specific genes, confirming their organ 
specificity. To determine whether VEGF-A might serve as an in vivo cell-fate 
switch for human ESC-derived Isl1-ECs, we established a novel approach using 
chemically modified mRNA as a platform for transient, yet highly efficient 
expression of paracrine factors in cardiovascular progenitors. Overexpression of 
VEGF-A promotes not only the endothelial specification but also engraftment, 
proliferation and survival (reduced apoptosis) of the human Isl1+ progenitors in 
vivo. The large-scale derivation of cardiac-specific human Isl1-ECs from human 
pluripotent stem cells, coupled with the ability to drive endothelial 
specification, engraftment, and survival following transplantation, suggest a 
novel strategy for vascular regeneration in the heart.