br Introduction Currently heart disease

Introduction Currently, heart disease is the leading cause of mortality in the industrialized world, partly due to the inability of the heart to regenerate in adults; and also the dietary and life style changes leading to a marked increase in the incidence of type II diabetes (for review, see Armstrong et al., 2013; Carvalheira et al., 2013; Ptaszek et al., 2012). Treatment options primarily address symptomatic manifestations; and current therapeutics can only delay the progression of heart failure until potential orthotopic heart transplantation is available (Ptaszek et al., 2012). Nevertheless, given the shortage of donor hearts for transplantation, there is an urgent need for novel therapies to repair severely diseased hearts. To address this issue, there is a growing interest in three research areas for heart regeneration including the use pluripotent stem cells (PSCs) for cell replacement therapy (for a review, see Addis and Epstein, 2013; Lui et al., 2012; Matsa et al., 2014; Vunjak-Novakovic et al., 2011; Xu et al., 2012), direct reprogramming of cardiac fibroblasts into myocardium in vivo (Fu et al., 2013; Ieda et al., 2010; Qian et al., 2012), or replication and reactivation of endogenous quiescent cardiovascular progenitor cells for differentiating into functional blood vessels and de novo Cilengitide cost (Chong et al., 2011; Smart et al., 2011; Zangi et al., 2013). In this review, we focus on reactivation of our endogenous regenerative capacity through paracrine mechanisms, and describe a new technological platform via synthetic modified mRNAs to express these factors in vivo in the heart following myocardial infarction.
Paracrine mechanisms: lessons from cell-based therapies Over the last decade, there has been a growing research interest in cell-based therapies with the hope of improving heart functions and attenuating adverse left ventricular (LV) remodeling in both ischemic and non-ischemic cardiomyopathy. Particularly, stem cells and progenitor cells which have the potential to self-renew and differentiate into functional cardiac muscle are attractive candidates for these purposes. The concept of cell-based regeneration has proven successful in clinical practice for over 50years (Soiffer, 2008), in which patients receive umbilical cord blood hematopoietic stem cells which replenish their entire repertoire of immune cells following bone marrow transplantation. To date, in cell-based studies, skeletal myoblasts (Taylor et al., 1998), bone marrow-derived mononuclear cells (Balsam et al., 2004; Murry et al., 2004), bone marrow- (Silva et al., 2005) or adipose- (Cai et al., 2009; Valina et al., 2007) derived mesenchymal stem cells, CD34+ hematopoietic stem cells (Botta et al., 2004; Wang et al., 2010), CD133+ endothelial progenitor cells (Stamm et al., 2007; Voo et al., 2008) and c-kit+ (Kajstura et al., 2005; Limana et al., 2005) or Sca-1+ (Wang et al., 2006) cardiac progenitor cells have been introduced into the damaged heart; however, results from all these pre-clinical and clinical trials remain ambiguous and therapies are yet to be proven conclusively effective (for a review, see Sanganalmath and Bolli, 2013). While transdifferentiation of non-cardiac cells into cardiomyocytes and vascular cells following transplantation into the damaged heart remains controversial (Balsam et al., 2004; Murry et al., 2004), recent studies have also challenged whether adult cardiac progenitor cells can robustly regenerate heart muscle in vivo in both experimental model systems (van Berlo et al., 2014) and clinical studies (Nowbar et al., 2014). Recently, human embryonic stem cells (hESCs) or induced pluripotent stem cells (hiPSCs), by virtue of their ability to self-renew and differentiate into almost all cell types of the body, have also been directed to differentiate into cardiomyocytes for transplantation studies (Cai et al., 2007; Caspi et al., 2007; Chong et al., 2014). Human ESC-derived cardiomyocytes were shown to attenuate LV remodeling and improve LV systolic function in rat hearts following myocardial infarction (MI) (Cai et al., 2007; Caspi et al., 2007). More recently, human ESC-derived cardiomyocytes were also demonstrated to generate extensive vascularized cardiac muscle in the infarcted hearts of non-human primates (Chong et al., 2014). Despite the advantage of using hESCs or hiPSCs to generate large numbers of human cardiomyocytes for clinical transplantation, these cells were quite diverse in terms of atrial/ventricular electrophysiological properties, as well as being partially mature and, therefore, proarrhythmic (Chong et al., 2014), resembling fetal-like rather than adult cardiomyocytes (for a review, see Lui KO et al., 2013). In addition, it is impossible to purify cardiomyocytes from human pluripotent stem cell systems without genetic markers and cardiomyocyte-specific cell surface markers that would allow complete purification have not been identified. Moreover, the success of cell-based therapies depends very much on the route of delivery, dosage and frequency of cell administration, and the degree of engraftment, long-term survival, lineage commitment and integration with the host myocardium (for a review, see Vunjak-Novakovic et al., 2011; Sanganalmath and Bolli, 2013). The optimal protocol is yet to be determined to gain the maximum benefits from transplanting each of the different cell types into the damaged heart.