Reprogramming toward Heart Regeneration: Stem Cells and Beyond Aitor Aguirre, Ignacio Sancho-Martinez, Juan Carlos Izpisua Belmonte  Cell Stem Cell  Volume 12, Issue 3, Pages 275-284 (March 2013) DOI: 10.1016/j.stem.2013.02.008 Copyright © 2013 Elsevier Inc. Terms and Conditions

Figure 1 Endogenous Regeneration in the Neonatal Mammalian Heart Neonatal mice (P1–P7) are able to regenerate the lost muscle by activating a cardiomyocyte-mediated proliferative organ-wide response (Porrello et al., 2011b) that restores complete function and leaves no scarring. These cardiomyocytes exhibit typical traits of dedifferentiation such as those observed in the zebrafish (Jopling et al., 2010). However, adult mice fail to regenerate the myocardial mass. Cell Stem Cell 2013 12, 275-284DOI: (10.1016/j.stem.2013.02.008) Copyright © 2013 Elsevier Inc. Terms and Conditions

Figure 2 Regeneration in the Adult Mammalian Heart Mammalian cardiomyocytes possess a very limited proliferative capacity. Under normal physiological conditions, two potential sources of cells contribute to the turnover of cardiomyocytes: cardiac progenitor cells and mature cardiomyocytes. This turnover is very low and decreases significantly with age (Bergmann et al., 2009; Senyo et al., 2013). Upon myocardial injury, the mammalian heart initiates an endogenous regenerative response, the extent of which is age dependent. An endogenous, cardiomyocytic hyperplasic response is observed but is very limited and restricted to the peri-infarct region (Senyo et al., 2013). These cardiomyocytes exhibit partially dedifferentiated traits. However, prolonged dedifferentiation can lead to hypertrophic cardiomyocytes and further contribute to heart failure (Kubin et al., 2011). In addition to cardiomyocytes, epicardial-derived cells might contribute to the myocardial mass and activation of inflammatory signals (Smart et al., 2011; Huang et al., 2012). Cell Stem Cell 2013 12, 275-284DOI: (10.1016/j.stem.2013.02.008) Copyright © 2013 Elsevier Inc. Terms and Conditions

Figure 3 Therapeutic Strategies to Improve Cardiac Function In Vivo Cardioprotective agents aiming at reducing and/or preventing the early deleterious effects of myocardial infarction (e.g., ischemia/reperfusion, inflammation, and fibrotic scarring) may constitute the gold standard approach toward repairing damage directly in the patient’s body. However, with this approach there is no replenishment of lost cardiac mass. Alternatively, the heart regeneration approaches recently described (Porrello et al., 2011a, 2011b; Eulalio et al., 2012; Smart et al., 2011; Zhou et al., 2008) aim to restore the cardiac tissue lost after the infarction by increasing the number of cardiomyocytes, either by mobilizing epicardial progenitors with cardiomyocyte differentiation potential or by activating endogenous regenerative pathways leading to dedifferentiation and proliferation of mature tissue-resident cardiomyocytes. In vivo reprogramming by lineage conversion of cardiac fibroblasts into cardiomyocytes is another attractive possibility to replenish myocardial tissue loss (Song et al., 2012; Qian et al., 2012). In this approach, cardiac fibroblasts can be reprogrammed to become cardiomyocytes by forced expression of GATA4, TBX5, MEF2C, and HAND2. Cell Stem Cell 2013 12, 275-284DOI: (10.1016/j.stem.2013.02.008) Copyright © 2013 Elsevier Inc. Terms and Conditions

Figure 4 Heart Repair Approaches to Improve Functional Recovery in Cardiac Disease These strategies rely on cell therapy to provide a source of cardiac progenitors capable of restoring the damaged tissue. Typically, cardiac progenitor cells and PSCs have been proposed for this purpose after expansion in culture (Moretti et al., 2006; Laugwitz et al., 2005). With the advent of reprogramming technologies, production of cardiomyocyte-like cells for therapy can also be achieved from other unrelated cell types by lineage conversion and/or from patient-specific iPSCs (Ieda et al., 2010). After expansion and generation of a sufficient number of cells, they are transplanted into the area of interest. Cell Stem Cell 2013 12, 275-284DOI: (10.1016/j.stem.2013.02.008) Copyright © 2013 Elsevier Inc. Terms and Conditions