Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages

• Published in: Nature (London) Vol. 460; no. 7251; pp. 113 - 117
• Main Authors: Bu, Lei, Martin-Puig, Silvia, Domian, Ibrahim J, Shao, Ying, Roberts, Drucilla J, Jiang, Xin, Chien, Kenneth R, Huang, Paul L, Caron, Leslie, Zhu, Shenjun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-07-2009; Nature Publishing Group
• Subjects: Artificial chromosomes; Biological and medical sciences; Cardiology. Vascular system; Cardiovascular disease; Cardiovascular diseases; Cell adhesion & migration; Cell Differentiation; Cell Division; Cell Line; Cell Lineage; Coculture Techniques; Embryonic stem cells; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Endothelial Cells - cytology; Fetus - cytology; Fetus - embryology; Genes; Genetic aspects; Heart; Heart - embryology; Heart cells; Homeodomain Proteins - metabolism; Humanities and Social Sciences; Humans; letter; LIM-Homeodomain Proteins; Medical sciences; multidisciplinary; Multipotent Stem Cells - cytology; Multipotent Stem Cells - metabolism; Muscle, Smooth - cytology; Myocardium - cytology; Myocytes, Cardiac - cytology; Physiological aspects; Proteins; Risk factors; Science; Science (multidisciplinary); Stem cells; Transcription Factors; Wnt Proteins - metabolism; Wnt3 Protein; United States; Heart; Human; Cell therapy; Stem cell; Multipotent cell; Cardiovascular disease; Circulatory system; Congenital cardiopathy; Progenitor cell
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature08191

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. 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. 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 differentiation into the three major cell types in the heart. These results lay the foundation for the generation of human model systems for cardiovascular disease and novel approaches for human regenerative cardiovascular medicine.