Despite contemporary medical treatments, heart failure remains a major cause of morbidity and mortality in developed countries (Go et al. 2014). Heart transplantation is a therapeutic option for patients at end-stage heart failure. However, because of the limited availability of donor organs, immune rejections, and infectious complications, alternative treatments are currently under evaluation. Transplantation of stem/progenitor cells have been considered alternative treatment for heart repair , attracting tremendous attention of basic scientists and clinicians (Forrester et al. 2003; Zimmermann et al. 2006; Sharma and Raghubir 2007). There are a number of clinical studies which have looked at cardiac function recovery via heart repair and regeneration by stem cell therapy in various clinical scenarios (Assmus et al. 2010; Bolli et al. 2011; Schaefer et al. 2011; Chugh et al. 2012; Makkar et al. 2012). The first report about stem cell therapy in heart failure utilized skeletal myoblasts in 1998 (Taylor et al. 1998). Later studies utilized total bone marrow (BM) stem cells (Perin et al. 2003; Willerson et al. 2010; Traverse et al. 2012, 2013), BM-derived mesenchymal stem cells (BM-MSCs) , endothelial progenitor cells (EPCs) , CD34+ and CD133+ cells (Sanganalmath and Bolli 2013). In add ition, the potential of embryonic stem cells (van Laake et al. 2009), adipose tissue-derived MSCs (Perin et al. 2014), hematopoietic stem cells and cardiac stem (CSC) and progenitor cells (CPCs ) (Smits et al. 2009) have been studied (Sanganalmath and Bolli 2013). The REPAIR-AMI trial suggested that intracoronary delivery of BM cells in patients with acute myocardial infarction (AMI) resulted in significant improvements in cardiac function, which were preserved over 2 years (Assmus et al. 2010). In contrast, t he BOOST trial , which was similarly constructed, showed based on 18-month and 5-year follow ups only an initial improvement with little sustained effect (Schaefer et al. 2011). The recent trials SCIPIO (Bolli et al. 2011; Chugh et al. 2012) and CADUCEUS (Makkar et al. 2012), showed promising results following the application of CSCs. Ta ken together, it appears that stem cells do contribute to cardiac repair or survival. However, it seems that the mechanism of action to date has not been differentiation into cardiomyocytes but indirect effects through the secretion of growth factors, at least for the cell types that are being used in clinical trials. Evidence is accumulating that these released factors direct a number of restorative processes including myocardial protection, neovascularization, and cardiac remodeling (Mirotsou et al. 2011). Novel delivery systems for enhancing the low stem cell engraftment and the importance of stem cell-mediated paracrine effects are discussed in Ch aps. 13 and 14, respectively. With respect to stem cell therapy, studies that applied CPCs or preparations of exogenous stem cells originating from BM or peripheral blood, both positive and negative studies suffer from small cohort sizes, lack of long-term clinical outcome as endpoint and mechanism for the beneficial effect of exogenously applied stem cells. Nevertheless, most, but not all, studies demonstrated reduced infarct size and recovery of heart function (reviewed in: (Sanganalmath and Bolli 2013)). Several ongoing multi-center trials will provide more insight into the clinical applicability of stem cell therapy and may shed more light on the mechanism of this strategy, e.g. the involvement of paracrine effects rather than differentiation. There are a vast number of novel biological pathways targeted by secretome through a variety of SRM (e.g. proteins, microRNA, growth factors, antioxidants, proteasomes and exosomes) and novel options for advanced therapies (ex-vivo cell-based gene therapy for stem cell rejuvenation, biom aterials, etc.), reviewed above that have reached the phase of pre-clinical application and could be ready for clinical translation, after several questions will be answered, including: (1) what are the best methods to maximize the effects of enhanced stem cell therapy in vivo and are new technologies required to achieve this?; (2) how do the properties of the stem cell secretome (composition and sustainability) change in vitro and following transplantation? and (3) how do the secretome or genetically-modified stem cells or stem cells in conjunction with biomaterials influence the function of the local microenvironment and resident stem cells post-transplantation, and how can we optimize these local effects? In summary, traditional stem cell therapy as well as advanced stem cell therapy preparations are promising options for cardiac regeneration and repair and state-of-art reached the clinical translation phase, however, results are still controversial for traditional stem cell therapy and new protocols still wait to be set-up the new stem cell preparations. The reasons for some negative studies of traditional stem cell therapy can be attributed to the presence of differe nt lim itations such as mechanism(s) of action of stem cells, inadequate recruitment of circulating or resident cardiac stem cells; poor capability of adult stem cells to differentiate into cardiomyocytes; elevated mortality of transplanted stem cells; age-related changes, including increased rates of apoptosis and senescence; anomalous electro-mechanical behavior of transplanted cells, in addition to optimal cell type(s), and dose, route, and frequency of cell administration (reviewed in Chap. 10).

It is now known that stem cells are not exempt from aging (Lopez-Otin et al. 2014). As a result, resident stem/progenitor cells in elderly humans may have a decreased capacity for repair in response to tissue injury (Issa 2014; Lopez-Otin et al. 2014; Rando and Wyss-Coray 2014). Nevertheless, it has become increasingly clear that it is possible to reverse stem cell aging by rejuvenating existing aged cells (Rando and Chang 2012). This has been possible because of better understanding of the genes and signaling involved in stem cell aging. Pim-1 kinase has been identified as an anti-senescence and anti-apoptotic factor in CSCs and MSCs (Borillo et al. 2010; Mohsin et al. 2012, 2013). Genetic modification of aged human CPCs with Pim-1 kinase results in remarkable rejuvenation of the CPCs associated with enhanced proliferation, i ncreased telomere lengths, and decreased susceptibility to replicative senesce nce (Mohsin et al. 2012, 2013). Notch plays also important roles in cardiac differentiation, regeneration and expansion of CPCs in mice (Yang et al. 2012; Nemir et al. 2014; Zhao et al. 2014) and zebrafish (Zhao et al. 2014). Activation of Notch restored “youthful” myogenic responses to satellite muscle cells isolated from 70-year-old humans, rendering them similar to cells from 20-year-old humans (Conboy and Rando 2012). The activation of telomere-telomerase axis contributes to cell survival and proliferation, and to prevent cellular senescence (Jan et al. 2011; Qu et al. 2011). A subpopulation of adipose tissue-derived MSCs (AT-MSCs) was recently identified that expresses high levels of myocardin (MYOCD), a nuclear transcription co-factor for myogenic and anti-apoptotic genes, and the cat alytic subunit of telomerase (i.e., telomerase reverse transcriptase or TERT ) (Madonna et al. 2012). AT-MSCs that co-express TERT and MYOCD have increased endogenous levels of octamer-binding transcription factor 4 (Oct-4), MYOCD, myocyte-specific enhancer f actor 2c (Mef2c), and homeobox protein Nkx2.5 (Madonna et al. 2012), high cardiovascular regenerative potential (Madonna et al. 2013), as well as decreased frequencies o f both spontaneous cell death and Fas-induced apoptosis (Madonna et al. 2013). The delivery of the TERT and MYOCD genes into AT-MSCs can restore MSCs from aged mice by increasing cell survival, proliferation, and smooth muscle myogenic differentiation in vitro (Madonna et al. 2013). Furthermore, the therapeutic efficacy of these rejuvenated cells was demonst rat ed in an in vivo hindlimb ischemia model (Madonna et al. 2013).

The following limitations of current approaches have been identified as yet to be solved: (1) inadequate recruitment of circulating or resident cardiac stem cells; (2) poor capability of adult stem cells to differentiate into cardiomyocytes; (3) elevated mortality of transplanted stem cells; (4) anomalous electro-mechanical behavior of transplanted cells after stimulation and the eventual onset of arrhythmias; (5) formation of new heart tissue structure differing from that of normal heart; and (6) diminished function of both resident and circulating st em/progenitor cells or even induced pluripotent stem cells with the onset of aging and age-related cardiovascular disease (Wang et al. 2011; Wu et al. 2011; Madonna et al. 2013; Pavo et al. 2014; Rohani et al. 2014). The question arose as to how stem cell therapy nevertheless can lead to recovery of cardiac function after ischemic injury. Attempts to answer this question have been made and rely on four possible different ways of using this strategy: 1. inject stem-derived cellular products—the so called stem cell therapy without the cells—which consists in the use of the collected types of molecules released by the stem cells, called the secretome or stem cell released molecules (SRM), including proteins, microRNA, growth factors, antioxidants, proteasomes and exosomes targeting a multitude of biological pathways through paracrine actions of the transplanted or activated stem cells; 2. boost the endogenous regenerative capacity of the adult heart, which retains some capacity of self-healing and self-renewal; 3. transplant genetically modified stem c ells, in which exogenous genes have been previously introduced by viral or not viral delivery vector, to exhibit delayed senescence, resistance to apoptosis and enhanced regenerative properties; 4. transplant stem cells in conjunction with biocompatible injectable biomaterials that are capable to enhance stem cell retention and survival through a variety of mechanisms. Large clinical studies will be necessary to get more insight into the clinical applicability of these novel stem cell strategies, which would be expected to offer further opportu nities to treatment of human patients with heart failure.