Wnt/β-catenin signaling promotes expansion of Isl-1 -: positive cardiac progenitor cells through regulation of FGF signaling

被引:203
作者
Cohen, Ethan David
Wang, Zhishan
Lepore, John J.
Lu, Min Min
Taketo, Makoto M.
Epstein, Douglas J.
Morrisey, Edward E. [1 ]
机构
[1] Univ Penn, Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA
[2] Grad Sch Med, Dept Pharmacol, Kyoto, Japan
[3] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA
[4] Univ Penn, Sch Med, Dept Cell & Dev Biol, Philadelphia, PA USA
关键词
ANTERIOR HEART FIELD; SMOOTH-MUSCLE-CELLS; BETA-CATENIN; GENE; PATHWAY; TRANSCRIPTION; MESODERM; ROLES; LUNG; MICE;
D O I
10.1172/JCI31731
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
The anterior heart field (AHF), which contributes to the outflow tract and right ventricle of the heart, is defined in part by expression of the LIM homeobox transcription factor Isl-1. The importance of Isl-1-positive cells in cardiac development and homeostasis is underscored by the finding that these cells are required for cardiac development and act as cardiac stem/progenitor cells within the postnatal heart. However, the molecular pathways regulating these cells' expansion and differentiation are poorly understood. We show that Isl-1-positive AHF progenitor cells in mice were responsive to Wnt/beta-catenin signaling, and these responsive cells contributed to the outflow tract and right ventricle of the heart. Loss of Wnt/beta-catenin signaling in the AHF caused defective outflow tract and right ventricular development with a decrease in Isl-1-positive progenitors and loss of FGF signaling. Conversely, Wnt gain of function in these cells led to expansion of Isl-l-positive progenitors with a concomitant increase in FGF signaling through activation of a specific set of FGF ligands including FGF3, FGF10, FGF16, and FGF20. These data reveal what we believe to be a novel Wnt-FGF signaling axis required for expansion of Isl-1-positive AHF progenitors and suggest future therapies to increase the number and function of these cells for cardiac regeneration.
引用
收藏
页码:1794 / 1804
页数:11
相关论文
共 40 条
[1]  
Brault V, 2001, DEVELOPMENT, V128, P1253
[2]   Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart [J].
Cai, CL ;
Liang, XQ ;
Shi, YQ ;
Chu, PH ;
Pfaff, SL ;
Chen, J ;
Evans, S .
DEVELOPMENTAL CELL, 2003, 5 (06) :877-889
[3]   FGF-20 and DKK1 are transcriptional targets of β-catenin and FGF-20 is implicated in cancer and development [J].
Chamorro, MN ;
Schwartz, DR ;
Vonica, A ;
Brivanlou, AH ;
Cho, KR ;
Varmus, HE .
EMBO JOURNAL, 2005, 24 (01) :73-84
[4]  
DasGupta R, 1999, DEVELOPMENT, V126, P4557
[5]   Intestinal polyposis in mice with a dominant stable mutation of the β-catenin gene [J].
Harada, N ;
Tamai, Y ;
Ishikawa, T ;
Sauer, B ;
Takaku, K ;
Oshima, M ;
Taketo, MM .
EMBO JOURNAL, 1999, 18 (21) :5931-5942
[6]   NEURONAL DETERMINATION WITHOUT CELL-DIVISION IN XENOPUS EMBRYOS [J].
HARRIS, WA ;
HARTENSTEIN, V .
NEURON, 1991, 6 (04) :499-515
[7]   Fgf8 is required for anterior heart field development [J].
Ilagan, Roger ;
Abu-Issa, Radwan ;
Brown, Doris ;
Yang, Yu-Ping ;
Jiao, Kai ;
Schwartz, Robert J. ;
Klingensmith, John ;
Meyers, Erik N. .
DEVELOPMENT, 2006, 133 (12) :2435-2445
[8]   Expression pattern of mouse sFRP-1 and mWnt-8 gene during heart morphogenesis [J].
Jaspard, B ;
Couffinhal, T ;
Dufourcq, P ;
Moreau, C ;
Duplàa, C .
MECHANISMS OF DEVELOPMENT, 2000, 90 (02) :263-267
[9]  
Katoh Y, 2006, INT J MOL MED, V17, P529
[10]   Molecular inroads into the anterior heart field [J].
Kelly, RG .
TRENDS IN CARDIOVASCULAR MEDICINE, 2005, 15 (02) :51-56