Wnt signaling exerts an antiproliferative effect on adult cardiac progenitor cells through IGFBP3.
BACKGROUND
Recent work in animal models and humans has demonstrated the presence of organ-specific progenitor cells required for the regenerative capacity of the adult heart. In response to tissue injury, progenitor cells differentiate into specialized cells, while their numbers are maintained through mechanisms of self-renewal. The molecular cues that dictate the self-renewal of adult progenitor cells in the heart, however, remain unclear.


OBJECTIVE
We investigate the role of canonical Wnt signaling on adult cardiac side population (CSP) cells under physiological and disease conditions.


RESULTS
CSP cells isolated from C57BL/6J mice were used to study the effects of canonical Wnt signaling on their proliferative capacity. The proliferative capacity of CSP cells was also tested after injection of recombinant Wnt3a protein (r-Wnt3a) in the left ventricular free wall. Wnt signaling was found to decrease the proliferation of adult CSP cells, both in vitro and in vivo, through suppression of cell cycle progression. Wnt stimulation exerted its antiproliferative effects through a previously unappreciated activation of insulin-like growth factor binding protein 3 (IGFBP3), which requires intact IGF binding site for its action. Moreover, injection of r-Wnt3a after myocardial infarction in mice showed that Wnt signaling limits CSP cell renewal, blocks endogenous cardiac regeneration and impairs cardiac performance, highlighting the importance of progenitor cells in maintaining tissue function after injury.


CONCLUSIONS
Our study identifies canonical Wnt signaling and the novel downstream mediator, IGFBP3, as key regulators of adult cardiac progenitor self-renewal in physiological and pathological states.
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Angelos
A
Oikonomopoulos
Konstantina-Ioanna
KI
Sereti
Frank
F
Conyers
Michael
M
Bauer
Annette
A
Liao
Jian
J
Guan
Dylan
D
Crapps
Jung-Kyu
JK
Han
Hanhua
H
Dong
Ahmad F
AF
Bayomy
Gabriel C
GC
Fine
Karen
K
Westerman
Travis L
TL
Biechele
Randall T
RT
Moon
Thomas
T
Force
Ronglih
R
Liao
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D006706:Homeostasis / Q000502:physiology; D066298:In Vitro Techniques; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology*; D060509:Wnt3A Protein / Q000494:pharmacology
D018972:Insulin-Like Growth Factor Binding Protein 3; D011994:Recombinant Proteins; D051153:Wnt Proteins; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse