Wnt Signaling Exerts an Antiproliferative Effect on Adult Cardiac Progenitor Cells Through IGFBP3

Abstract

Rationale 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 Herein, we investigate the role of canonical Wnt signaling on adult cardiac side population (CSP) cells under physiological and disease conditions. Methods and Results CSP cells isolated from C57BL/6J mice were utilized to study the effects of canonical Wnt signaling on their proliferative capacity. The proliferative capacity of CSP cells was also tested following 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 anti-proliferative 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 following 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.

Regenerating new heart with stem cells

“…The recognition that the adult heart harbors a compartment of multipotent c-kit-positive cardiac stem cells (CSCs) (15)(16)(17)(18)(19)(20)(21)(22)(23) and other progenitor cell classes (24)(25)(26)(27)(28)(29) capable of differentiating into cardiomyocytes and coronary vessels has raised the challenging question concerning their embryologic origin and role in cardiac cell turnover and regeneration. CSCs are stored in interstitial structures with the characteristics of stem cell niches and can divide symmetrically and asymmetrically, with the ability to self-renew and form a committed progeny (17,21,30).…”

Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells

“…Wnt signal strength has been shown to control the balance between self renewal and differentiation (46). We found that EC-educated MniPSC-MPP downregulated targets of the Wnt/β-catenin pathway relative to EC-naive MniPSC-MPP, which is not surprising given that ECs express Wnt pathway inhibitors DKK1 (47), DKK3 (15), IGFPB2 (48), and IGFBP3 (49). Wnt signaling has been shown to regulate the Notch pathway in normal (50)(51)(52) and malignant hematopoiesis (53,54).…”

Cellular and Molecular Characterization of Human Cardiac Stem Cells Reveals Key Features Essential for Their Function and Safety

“…The upregulation of MYH11 might suggest spontaneous differentiation of cells into smooth muscle cells (one of the cell lines that CSCs are committed to) through passages. It was shown that members of IGFBP family such as IGFBP4 and IGFBP3, which are independent of binding to insulin growth factor, are involved in the processes of cardiogenesis [48][49][50]. A new subset of cardiac precursor cells that expressed insulin-like growth factor 1 receptor (IGF-1R) was found to have higher proliferation and myogenic differentiation potential compared with other CSCs subgroups [51].…”