Abstract 18240: Wnt Signaling Negatively Regulates the Proliferation of Adult Cardiac Progenitor Cells
Recent studies have demonstrated the existence of endogenous cardiac stem/progenitor cells capable of regenerating damaged myocardium following myocardial infarction (MI). Cardiac side population (CSP) cells are cardiac precursors found in the adult myocardium, which are able to differentiate into functional cardiomyocytes both in vitro and in vivo, following MI. In response to local tissue injury, CSP cells are maintained through a process of self-renewal. The molecular signals that control the self-renewal of adult progenitor cells in the heart remain unclear. Canonical Wnt signaling pathway has been implicated in the regulation of tumor progression, development and regeneration in various tissues. The goal of this study was to determine the effects of Wnt signaling pathway on the homeostasis of adult CSP cells under normal and disease conditions.
Results: In contrast to previous work in embryonic or early post-natal cardiac stem cells, we reveal that Wnt signaling negatively regulates adult CSP progenitor cell proliferation, both in vitro and in vivo through suppression of cell cycle progression. Furthermore, we demonstrate that Wnt signaling exerts its anti-proliferative effect through the activation of insulin-like growth factor binding protein 3 (IGFBP3). Administration of recombinant Wnt3a protein in the infarct/border zone of mouse hearts, following MI decreases the amount of cardiac CSP cells and impairs the endogenous cardiac regenerative capacity, as evidenced by the decreased number of BrdU positive cardiomyocytes. Reduction of cardiac regenerative capacity mediates adverse effects on post-MI remodeling and performance.
Conclusion: Our data demonstrate that Wnt signaling represents an effective negative regulator of adult cardiac progenitor cell proliferation, under physiologic conditions and post-MI. Inhibition of Wnt signaling may be considered as an approach to promote cardiac regeneration following ischemic injury.
- © 2011 by American Heart Association, Inc.