Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages

ISL1 progenitors are all heart Recent studies in mice identified multipotent embryonic ISL1 + (Islet 1 expressing) progenitor cells as capable of contributing to all of the major cell types in the heart. Human cardiogenesis is thought to involve more divergent pathways. Now a diverse set of human fetal ISL1 + cardiovascular progenitor populations with multipotent capability has been identified in the right atrium and outflow tract of the developing human heart. Transgenic and gene-targeting techniques applied to human embryonic stem cell lines show that purified populations of these primordial progenitors are capable of self-renewal and expansion prior to differentiation into the three major cell types in the heart — the cardiomyocytes, smooth muscle and endothelia. This has relevance for the production of human models for cardiovascular disease and potentially for human regenerative medicine. Studying the mechanisms underlying the diversification of human heart cell lineages has been hampered by the lack of genetic tools to purify early cardiac progenitors and define their developmental potential. By using independent transgenic and gene-targeting approaches in human embryonic stem cell lines, it has now been possible to show that populations of these primordial progenitors are capable of self-renewal and expansion prior to differentiation into the three major cell types in the heart. The generation and expansion of diverse cardiovascular cell lineages is a critical step during human cardiogenesis, with major implications for congenital heart disease. Unravelling the mechanisms for the diversification of human heart cell lineages has been hampered by the lack of genetic tools to purify early cardiac progenitors and define their developmental potential 1 , 2 , 3 , 4 . Recent studies in the mouse embryo have identified a multipotent cardiac progenitor that contributes to all of the major cell types in the murine heart 5 , 6 , 7 , 8 . In contrast to murine development, human cardiogenesis has a much longer onset of heart cell lineage diversification and expansion, suggesting divergent pathways. Here we identify a diverse set of human fetal ISL1 + cardiovascular progenitors that give rise to the cardiomyocyte, smooth muscle and endothelial cell lineages. Using two independent transgenic and gene-targeting approaches in human embryonic stem cell lines, we show that purified ISL1 + primordial progenitors are capable of self-renewal and expansion before differen