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

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: We investigate the role of canonical Wnt signaling on adult cardiac side population (CSP) cells under physiological and disease conditions. 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. A ccumulating evidence over the past decade in both humans and animal models has documented the presence of endogenous progenitor cells in adult myocardium. 1– 6 In response to local tissue injury, cardiac progenitor cells differentiate into specialized cells, while the pool of progenitor cells is maintained, in part, through self-renewal and enhanced proliferation. 7,8 However, the molecular cues and signaling pathways that dictate the homeostasis of adult progenitor cells and in particular their self-renewal, in physiological and pathological states, remain unclear. Wnt ligands constitute a family of 19 secreted glycopro-teins that act as key regulators of cellular function during development, adulthood, and disease. 9,10 Several reports have proposed time and context dependent roles for Wnt signaling in cardiogenesis and progenitor cell biology. 11 Studies in chick and Xenopus embryos have demonstrated that inhibition of Wnt signaling is required for cardiac differentiation , 12,13 whereas Wnt signaling has also been found to promote cardiomyogenesis in Drosophila and embryonic carcinoma P19 cells. 14,15 Moreover, early in gastrulation, Wnt ligands activate a cardiac differentiation program, whereas at later stages they act as potent inhibitors of the cardiomyo-genic differentiation. 16,17 Recent genetic studies have demonstrated that the canonical Wnt signaling cascade promotes the proliferation of neonatal and embryonic Isl-1 ϩ cardiac progenitors in vitro and in vivo. 18 –20 Little is known, however, regarding the role of Wnt signals in modulating adult progenitor cell populations. Side population (SP) cells were initially identified based on their unique ability to efflux the DNA binding dye Hoechst 33342, 21 and were found to retain the long-term regenerative potential of bone marrow. Subsequently, SP cells were identified in various adult tissues/organs including adult myocardium. 22 Cardiac SP (CSP) cells are enriched in Sca1 but do not express c-kit …