Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages.
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.
Bu
Lei
L
Cardiovascular Research Center, Massachusetts General Hospital, Charles River Plaza/CPZN 3208, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Jiang
Xin
X
Martin-Puig
Silvia
S
Caron
Leslie
L
Zhu
Shenjun
S
Shao
Ying
Y
Roberts
Drucilla J
DJ
Huang
Paul L
PL
Domian
Ibrahim J
IJ
Chien
Kenneth R
KR
D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D019070:Cell Lineage; D018920:Coculture Techniques; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology; D005333:Fetus / Q000166:cytology / Q000196:embryology; D006321:Heart / Q000196:embryology; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D060850:LIM-Homeodomain Proteins; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D009130:Muscle, Smooth / Q000166:cytology; D009206:Myocardium / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000166:cytology; D014157:Transcription Factors; D051153:Wnt Proteins / Q000378:metabolism; D060508:Wnt3 Protein
D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D060508:Wnt3 Protein; C063843:insulin gene enhancer binding protein Isl-1