The renewal and differentiation of Isl1+ cardiovascular progenitors are controlled by a Wnt/beta-catenin pathway.
Isl1(+) cardiovascular progenitors and their downstream progeny play a pivotal role in cardiogenesis and lineage diversification of the heart. The mechanisms that control their renewal and differentiation are largely unknown. Herein, we show that the Wnt/beta-catenin pathway is a major component by which cardiac mesenchymal cells modulate the prespecification, renewal, and differentiation of isl1(+) cardiovascular progenitors. This microenvironment can be reconstituted by a Wnt3a-secreting feeder layer with ES cell-derived, embryonic, and postnatal isl1(+) cardiovascular progenitors. In vivo activation of beta-catenin signaling in isl1(+) progenitors of the secondary heart field leads to their massive accumulation, inhibition of differentiation, and outflow tract (OFT) morphogenic defects. In addition, the mitosis rate in OFT myocytes is significantly reduced following beta-catenin deletion in isl1(+) precursors. Agents that manipulate Wnt signals can markedly expand isl1(+) progenitors from human neonatal hearts, a key advance toward the cloning of human isl1(+) heart progenitors.
Qyang
Yibing
Y
Cardiovascular Research Center, Massachusetts General Hospital, Charles River Plaza/CPZN 3208, 185 Cambridge Street, Boston, MA 02114-2790, USA.
Martin-Puig
Silvia
S
Chiravuri
Murali
M
Chen
Shuibing
S
Xu
Huansheng
H
Bu
Lei
L
Jiang
Xin
X
Lin
Lizhu
L
Granger
Anne
A
Moretti
Alessandra
A
Caron
Leslie
L
Wu
Xu
X
Clarke
Jonathan
J
Taketo
Makoto M
MM
Laugwitz
Karl-Ludwig
KL
Moon
Randall T
RT
Gruber
Peter
P
Evans
Sylvia M
SM
Ding
Sheng
S
Chien
Kenneth R
KR
D000818:Animals; D002319:Cardiovascular System / Q000166:cytology / Q000196:embryology*; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D004622:Embryo, Mammalian / Q000502:physiology; D005260:Female; D006321:Heart / Q000196:embryology / Q000502:physiology; D006330:Heart Defects, Congenital / Q000503:physiopathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D060850:LIM-Homeodomain Proteins; D008297:Male; D051379:Mice; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014157:Transcription Factors; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C063843:insulin gene enhancer binding protein Isl-1