Stem cell therapy has emerged as a promising tool for the treatment of a variety of diseases. Previously, we have shown that Akt-modified mesenchymal stem cells mediate tissue repair through paracrine mechanisms. Using a comprehensive functional genomic strategy, we show that secreted frizzled related protein 2 (Sfrp2) is the key stem cell paracrine factor that mediates myocardial survival and repair after ischemic injury. Sfrp2 is known to modulate Wnt signaling, and we demonstrate that cardiomyocytes treated with secreted frizzled related protein increase cellular ␤-catenin and up-regulate expression of antiapoptotic genes. These findings reveal the key role played by Sfrp2 in mediating the paracrine effects of Akt-mesenchymal stem cells on tissue repair and identify modulation of Wnt signaling as a therapeutic target for heart disease.D espite major advances in our understanding and therapy of coronary artery disease, myocardial infarction remains a major cause of mortality and morbidity in the United States. The limited ability of the damaged heart to regenerate and replace dead myocardium leads to the devastating sequelae of congestive heart failure. The recent interests in the development of cell-based therapeutic strategies are aimed at replenishing the diminished myocyte mass (1). Such cell-based strategies have used a variety of stem and progenitor cells, including skeletal muscle myoblasts, embryonic stem cells, resident cardiac stem cells, mesenchymal stem cells (MSCs), endothelial progenitor cells, and bone marrowderived mononuclear cells (2). Although the majority of animal and preliminary human studies of cell-based therapy shows an overall improvement in cardiac function when administered to hearts after acute infarction, the effects generally are modest, and the mechanisms underlying such an observed improvement are far from clear (3). Postulated mechanisms include differentiation of transplanted cells or resident cardiac stem cells into cardiomyocytes (4), fusion between donor cells and host cardiomyocytes (5), and/or improved tissue perfusion attributable to enhanced donor cell-derived angiogenesis (6).We recently have reported that intracardiac implantation of genetically engineered MSCs overexpressing the Akt gene (AktMSCs) yielded dramatic diminution of infarct size and restoration of cardiac function in rodent hearts after myocardial injury (7). We observed that these salutary effects occurred as early as 72 h after Akt-MSC implantation (8). Moreover, we demonstrated that Akt-MSC-conditioned medium provided survival signal to adult ventricular myocytes against hypoxia-induced apoptosis in vitro and upon injection into infarcted hearts, dramatically limited infarct size, and prevented ventricular dysfunction in vivo (8). Accordingly, we hypothesized that Akt-MSCs achieve their beneficial effects in part through enhancing early survival of the ischemic myocardium. Furthermore, we postulated that the prosurvival effects of AktMSCs on ischemic myocardium are paracrine in nature and mediated by ...

Abstract-Endothelial dysfunction and cell loss are prominent features in cardiovascular disease. Endothelial progenitor cells (EPCs) originating from the bone marrow play a significant role in neovascularization of ischemic tissues and in re-endothelialization of injured blood vessels. Several studies have shown the therapeutic potential of EPC transplantation in rescue of tissue ischemia and in repair of blood vessels and bioengineering of prosthetic grafts. Recent small-scale trials have provided preliminary evidence of feasibility, safety, and efficacy in patients with myocardial and critical limb ischemia. However, several studies have shown that age and cardiovascular disease risk factors reduce the availability of circulating EPCs (CEPCs) and impair their function to varying degrees. In addition, the relative scarcity of CEPCs limits the ability to expand these cells in sufficient numbers for some therapeutic applications. Priority must be given to the development of strategies to enhance the number and improve the function of CEPCs. Furthermore, alternative sources of EPC such as chord blood need to be explored. Strategies for improvement of cell adhesion, survival, and prevention of cell senescence are also essential to ensure therapeutic viability. Genetic engineering of EPCs may be a useful approach to developing these cells into efficient therapeutic tools. In the clinical arena there is pressing need to standardize the protocols for isolation, culture, and therapeutic application of EPC. Large-scale multi-center randomized trials are required to evaluate the long-term safety and efficacy of EPC therapy. Despite these hurdles, the outlook for EPC-based therapy for cardiovascular disease is promising. (Hypertension. 2005;46:7-18.)