Several studies have suggested that Secreted Frizzled-related protein 2 (Sfrp2), a Wnt pathway inhibitor, is a key mediator of myocardial wound repair and has been shown to inhibit myocyte apoptosis, induce angiogenesis and inhibit fibrosis. In several model systems, Sfrp2 is a regulator of differentiation yet no studies have been performed that directly address the significance of Sfpr2 in cardiomyocyte renewal and the role of Sfpr2 in cardiac progenitor cell (CPC) activation, proliferation and differentiation remains to be elucidated. The regulation of CPC expansion and differentiation is a fundamental but yet unclear aspect of cardiovascular biology and regenerative medicine. Our preliminary studies, both in vitro and in vivo, suggest CPCs are responsive to Wnt/Sfrp2 signaling. Our data suggest that Sfrp2 inhibits canonical Wnt3a signaling and enhances differentiation in adult c-Kit+/Sca1+ CPCs. Thus, the role of the Sfrp2 in modulation of adult cardiomyocyte renewal by a potential Sfpr2/Wnt interaction poses an intriguing question. To address this, we hypothesize that Sfrp2, by modulating Wnt canonical pathway, is a key regulator of cardiac progenitor proliferation and lineage specification. To test this hypothesis, using cultured CPCs, we will investigate in vitro the importance of Sfpr2 and Wnt3a on CPC proliferation and differentiation, and elucidate the role of the Wnt/b-catenin canonical signaling pathway. In vivo, we will extend these studies by evaluating the role of Sfrp2 on cardiomyocyte renewal by examining its effects on endogenous CPC fate. We will use a genetic fate-mapping study and lineage tracing protocols to examine the proliferation and activation of endogenous cardiac stem cells, the differentiation of these cells to cardiac mocytes and determine the role of Sfrp2 on these processes and we will enquire about the importance of the Wnt/b-catenin canonical signaling pathway in mediating the Sfrp2 effects on CPCs in vivo. At the conclusion of this research proposal we will have characterized the role of Sfrp2 signaling in adult cardiac stem cells providing novel insights about the pathways that regulate these cells and opening new opportunities about their modulation ex vivo or in vivo for therapeutic purposes.
STATEMENT Heart failure is a leading cause of mortality worldwide. Patients receive symptomatic treatment, and future biologically targeted therapy will depend on the discovery of new pathways that initiate, promote or potentially reverse the onset of heart muscle failure. In this grant application we propose to characterize Sfrp2 an inhibitor of Wnt signaling which, as our preliminary results indicate, is involved in activation and differentiation of cardiac progenitor cells. These studies should open new avenues for the better understanding of the mechanisms of heart failure and may lead to the potential development of novel therapeutic drugs for myocardial injury, hypertrophy and heart failure.
|Jayawardena, Tilanthi M; Finch, Elizabeth A; Zhang, Lunan et al. (2015) MicroRNA induced cardiac reprogramming in vivo: evidence for mature cardiac myocytes and improved cardiac function. Circ Res 116:418-24|
|Hodgkinson, Conrad P; Gomez, Jose A; Payne, Alan J et al. (2014) Abi3bp regulates cardiac progenitor cell proliferation and differentiation. Circ Res 115:1007-16|
|Huang, Jing; Guo, Jian; Beigi, Farideh et al. (2014) HASF is a stem cell paracrine factor that activates PKC epsilon mediated cytoprotection. J Mol Cell Cardiol 66:157-64|
|Ardhanareeswaran, Karthikeyan; Mirotsou, Maria (2013) Lung stem and progenitor cells. Respiration 85:89-95|
|Beigi, Farideh; Schmeckpeper, Jeffrey; Pow-Anpongkul, Pete et al. (2013) C3orf58, a novel paracrine protein, stimulates cardiomyocyte cell-cycle progression through the PI3K-AKT-CDK7 pathway. Circ Res 113:372-80|
|Wang, Hao; Gomez, Jose A; Klein, Sabine et al. (2013) Adult renal mesenchymal stem cell-like cells contribute to juxtaglomerular cell recruitment. J Am Soc Nephrol 24:1263-73|
|Jayawardena, Tilanthi M; Egemnazarov, Bakytbek; Finch, Elizabeth A et al. (2012) MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res 110:1465-73|
|Mirotsou, Maria; Jayawardena, Tilanthi M; Schmeckpeper, Jeffrey et al. (2011) Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J Mol Cell Cardiol 50:280-9|
|Hodgkinson, Conrad P; Gomez, José A; Mirotsou, Maria et al. (2010) Genetic engineering of mesenchymal stem cells and its application in human disease therapy. Hum Gene Ther 21:1513-26|
|Huang, Jing; Zhang, Zhiping; Guo, Jian et al. (2010) Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium. Circ Res 106:1753-62|
Showing the most recent 10 out of 14 publications