The epidemic of heart failure has stimulated interest in understanding cardiac regeneration. Evidence has been reported supporting regeneration via transplantation of multiple cell types, as well as replication of postmitotic cardiomyocytes. In addition, the adult myocardium harbors endogenous c-kit(pos) cardiac stem cells (eCSCs), whose relevance for regeneration is controversial. Here, using different rodent models of diffuse myocardial damage causing acute heart failure, we show that eCSCs restore cardiac function by regenerating lost cardiomyocytes. Ablation of the eCSC abolishes regeneration and functional recovery. The regenerative process is completely restored by replacing the ablated eCSCs with the progeny of one eCSC. eCSCs recovered from the host and recloned retain their regenerative potential in vivo and in vitro. After regeneration, selective suicide of these exogenous CSCs and their progeny abolishes regeneration, severely impairing ventricular performance. These data show that c-kit(pos) eCSCs are necessary and sufficient for the regeneration and repair of myocardial damage.

Key Words: vascular smooth muscle cells Ⅲ microRNA Ⅲ miR-133 Ⅲ smooth muscle differentiation Ⅲ vascular remodeling V ascular smooth muscle cells (VSMCs) within adult blood vessels proliferate at a very low rate, exhibit very low synthetic activity, and express a unique repertoire of contractile proteins, ion channels, and signaling molecules. 1 Unlike skeletal muscle and cardiac muscle, which consist of terminally differentiated cells, adult VSMCs retain remarkable plasticity and can undergo rather profound and reversible changes in phenotype and growth properties in response to changes in local environmental cues. Salient examples of VSMC plasticity can be seen in response to vascular injury when VSMCs dramatically increase their proliferation, migration, and synthetic capacity, playing a critical role in vascular repair. 1,2 A detrimental consequence of the high degree of plasticity exhibited by adult VSMCs is that it can lead to an adverse phenotypic switch and acquisition of characteristics that can contribute to development or progression of vascular disease in humans, including atherosclerosis, restenosis, cancer, and hypertension. [1][2][3] VSMC phenotypic modulation is characterized by significant changes in gene expression patterns, matrix and cytokine production, contractility, and growth state, ultimately leading to their switch from a synthetic to a proliferative phenotype.Original received January 3, 2011; revision received August 8, 2011; accepted August 9, 2011. In July 2011, the average time from submission to first decision for all original research papers submitted to Circulation Research was 13.5 days.From Thus, understanding the regulatory mechanisms underlying the VSMC phenotypic switch is of paramount importance. [1][2][3] One of the key breakthroughs for the study of gene expression regulation has recently been the discovery of microRNAs (miRNAs or miRs) and their role in gene silencing through mRNA degradation or translational inhibition. 4,5 Increasing evidence indicates that miRNAs regulate key genetic programs in cardiovascular biology, physiology, and disease. 4,5 In particular, miR-21, -143, -145, -221, -222 have all been implicated to play a role in VSMC function and phenotypic plasticity. 6 -11 More recently, 2 articles demonstrated that miR-1 is induced by myocardin overexpression in human SMCs, contributing to myocardin-dependent reduction of human SMC growth in vitro. 12,13 miR-133a-1/miR-1-2 and miR133a-2/miR-1-1 are 2 bicistronic miRNA clusters reported to be specifically expressed in cardiac and skeletal muscle. 4,5 A third bicistronic miRNA cluster, comprising miR-206 and miR-133b, is expressed specifically in skeletal muscle but not in the heart. 4,5 miR-1 (miR-1-1/miR-1-2) and miR-133 (miR133a-1/miR-133a-2) play essential roles in cardiac and skeletal muscle development, physiology, and disease 4,5 ; however, their functions in VSMCs and vascular disease are largely unknown. Thus, the aim of the present study was to evaluate the role, if any, of miR-1 and miR-133 in V...

In an animal model of AMI relevant to the human disease, intracoronary administration of IGF-1/HGF is a practical and effective strategy to reduce pathological cardiac remodeling, induce myocardial regeneration, and improve ventricular function.

Exercise training fosters the health and performance of the cardiovascular system, and represents nowadays a powerful tool for cardiovascular therapy. Exercise exerts its beneficial effects through reducing cardiovascular risk factors, and directly affecting the cellular and molecular remodelling of the heart. Traditionally, moderate endurance exercise training has been viewed to determine a balanced and revertible physiological growth, through cardiomyocyte hypertrophy accompanied by appropriate neoangiogenesis (the Athlete's Heart). These cellular adaptations are due to the activation of signalling pathways and in particular, the IGF-1/IGF-1R/Akt axis appears to have a major role. Recently, it has been shown that physical exercise determines cardiac growth also through new cardiomyocyte formation. Accordingly, burgeoning evidence indicates that exercise training activates circulating, as well as resident tissue-specific cardiac, stem/progenitor cells. Dissecting the mechanisms for stem/progenitor cell activation with exercise will be instrumental to devise new effective therapies, encompassing myocardial regeneration for a large spectrum of cardiovascular diseases.

AimsIt is a dogma of cardiovascular pathophysiology that the increased cardiac mass in response to increased workload is produced by the hypertrophy of the pre-existing myocytes. The role, if any, of adult-resident endogenous cardiac stem/progenitor cells (eCSCs) and new cardiomyocyte formation in physiological cardiac remodelling remains unexplored.Methods and resultsIn response to regular, intensity-controlled exercise training, adult rats respond with hypertrophy of the pre-existing myocytes. In addition, a significant number (∼7%) of smaller newly formed BrdU-positive cardiomyocytes are produced by the exercised animals. Capillary density significantly increased in exercised animals, balancing cardiomyogenesis with neo-angiogenesis. c-kitpos eCSCs increased their number and activated state in exercising vs. sedentary animals. c-kitpos eCSCs in exercised hearts showed an increased expression of transcription factors, indicative of their commitment to either the cardiomyocyte (Nkx2.5pos) or capillary (Ets-1pos) lineages. These adaptations were dependent on exercise duration and intensity. Insulin-like growth factor-1, transforming growth factor-β1, neuregulin-1, bone morphogenetic protein-10, and periostin were significantly up-regulated in cardiomyocytes of exercised vs. sedentary animals. These factors differentially stimulated c-kitpos eCSC proliferation and commitment in vitro, pointing to a similar role in vivo.ConclusionIntensity-controlled exercise training initiates myocardial remodelling through increased cardiomyocyte growth factor expression leading to cardiomyocyte hypertrophy and to activation and ensuing differentiation of c-kitpos eCSCs. This leads to the generation of new myocardial cells. These findings highlight the endogenous regenerative capacity of the adult heart, represented by the eCSCs, and the fact that the physiological cardiac adaptation to exercise stress is a combination of cardiomyocyte hypertrophy and hyperplasia (cardiomyocytes and capillaries).