Multipotent embryonic isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification.
Cardiogenesis requires the generation of endothelial, cardiac, and smooth muscle cells, thought to arise from distinct embryonic precursors. We use genetic fate-mapping studies to document that isl1(+) precursors from the second heart field can generate each of these diverse cardiovascular cell types in vivo. Utilizing embryonic stem (ES) cells, we clonally amplified a cellular hierarchy of isl1(+) cardiovascular progenitors, which resemble the developmental precursors in the embryonic heart. The transcriptional signature of isl1(+)/Nkx2.5(+)/flk1(+) defines a multipotent cardiovascular progenitor, which can give rise to cells of all three lineages. These studies document a developmental paradigm for cardiogenesis, where muscle and endothelial lineage diversification arises from a single cell-level decision of a multipotent isl1(+) cardiovascular progenitor cell (MICP). The discovery of ES cell-derived MICPs suggests a strategy for cardiovascular tissue regeneration via their isolation, renewal, and directed differentiation into specific mature cardiac, pacemaker, smooth muscle, and endothelial cell types.
Moretti
Alessandra
A
Massachusetts General Hospital - Cardiovascular Research Center, Charles River Plaza/CPZN 3208, 185 Cambridge Street, Boston, MA 02114, USA.
Caron
Leslie
L
Nakano
Atsushi
A
Lam
Jason T
JT
Bernshausen
Alexandra
A
Chen
Yinhong
Y
Qyang
Yibing
Y
Bu
Lei
L
Sasaki
Mika
M
Martin-Puig
Silvia
S
Sun
Yunfu
Y
Evans
Sylvia M
SM
Laugwitz
Karl-Ludwig
KL
Chien
Kenneth R
KR
D000818:Animals; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D019070:Cell Lineage; D002999:Clone Cells; D053595:Embryonic Stem Cells / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology*; D006321:Heart / Q000196:embryology; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D060850:LIM-Homeodomain Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D039902:Multipotent Stem Cells / Q000502:physiology*; D009206:Myocardium / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D014157:Transcription Factors
D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1