The mammalian heart has a very limited regenerative capacity and, hence, heals by scar formation. Recent reports suggest that haematopoietic stem cells can transdifferentiate into unexpected phenotypes such as skeletal muscle, hepatocytes, epithelial cells, neurons, endothelial cells and cardiomyocytes, in response to tissue injury or placement in a new environment. Furthermore, transplanted human hearts contain myocytes derived from extra-cardiac progenitor cells, which may have originated from bone marrow. Although most studies suggest that transdifferentiation is extremely rare under physiological conditions, extensive regeneration of myocardial infarcts was reported recently after direct stem cell injection, prompting several clinical trials. Here, we used both cardiomyocyte-restricted and ubiquitously expressed reporter transgenes to track the fate of haematopoietic stem cells after 145 transplants into normal and injured adult mouse hearts. No transdifferentiation into cardiomyocytes was detectable when using these genetic techniques to follow cell fate, and stem-cell-engrafted hearts showed no overt increase in cardiomyocytes compared to sham-engrafted hearts. These results indicate that haematopoietic stem cells do not readily acquire a cardiac phenotype, and raise a cautionary note for clinical studies of infarct repair.

Abstract-Although rapid progress is being made in many areas of molecular cardiology, issues pertaining to the origins of heart-forming cells, the mechanisms responsible for cardiogenic induction, and the pathways that regulate cardiomyocyte proliferation during embryonic and adult life remain unanswered. In the present study, we review approaches and studies that have shed some light on cardiomyocyte cell cycle regulation. For reference, an initial description of cardiomyogenic induction and morphogenesis is provided, which is followed by a summary of published cell cycle analyses during these stages of cardiac ontology. A review of studies examining cardiomyocyte cell cycle analysis and de novo cardiomyogenic induction in the adult heart is then presented. Finally, studies in which cardiomyocyte cell cycle activity was experimentally manipulated in vitro and in vivo are reviewed. It is hoped that this compilation will serve to stimulate thought and experimentation in this intriguing area of cardiomyocyte cell biology. Key Words: cardiomyocyte proliferation Ⅲ cardiac myocyte apoptosis Ⅲ heart regeneration Ⅲ gene targeting Ⅲ transgenic mice S tudies using embryos from different species (fly, chick, zebrafish, xenopus, and mouse) have shed some light on the cardiogenic induction process. During gastrulation of the chick embryo, primitive streak cells migrate to the lateral plate mesoderm. Those cells that migrate to the anterior lateral plate mesoderm are destined to form heart tissue. [1][2][3] On migration, these cells proliferate extensively 4 while remaining in close contact with the anterior endoderm 3 (a prerequisite for their subsequent cardiomyogenic induction). 5 Recent studies have elegantly identified several growth factors that regulate cardiomyogenic induction of the precursor cells in the anterior mesoderm. These include molecules that promote cardiomyogenic induction (BMPs, FGFs, inhibitors of Wnt family of morphogens such as Crescent, Dkk-1, and glycogen synthase kinase-3), as well as molecules that inhibit the process (Wnt family of morphogens, noggin, and chordin). 6 -9 The failure of these growth factors to promote cardiomyogenic induction in more primitive precursor cells indicates that additional as of yet unidentified factors participate in the process.In contrast to our somewhat limited understanding of the inductive clues that mediate cardiomyogenic lineage determination, the morphogenetic transformation of the primitive heart into a 4-chambered structure is fairly well characterized. The heart field initially forms as a crescent shaped structure in the anterior part of the embryo that later develops into a linear tube. 10 The tubular heart undergoes segmentation along the anterior-posterior axis, followed by rightward looping. This process results in the formation of the right and left ventricles, the atrioventricular canal, the sinoatrial, and the outflow tract segments. 11,12 Subsequently, the ventral side of the heart tube rotates and forms the outer curvature of the heart, with the d...

Abstract-Restriction point transit and commitment to a new round of cell division is regulated by the activity of cyclin-dependent kinase 4 and its obligate activating partners, the D-type cyclins. In this study, we examined the ability of D-type cyclins to promote cardiomyocyte cell cycle activity. Adult transgenic mice expressing cyclin D1, D2, or D3 under the regulation of the ␣ cardiac myosin heavy chain promoter exhibited high rates of cardiomyocyte DNA synthesis under baseline conditions. Cardiac injury in mice expressing cyclin D1 or D3 resulted in cytoplasmic cyclin D accumulation, with a concomitant reduction in the level of cardiomyocyte DNA synthesis. In contrast, cardiac injury in mice expressing cyclin D2 did not alter subcellular cyclin localization. Consequently, cardiomyocyte cell cycle activity persisted in injured hearts expressing cyclin D2, ultimately resulting in infarct regression. These data suggested that modulation of D-type cyclins could be exploited to promote regenerative growth in injured hearts. Key Words: cardiomyocyte proliferation Ⅲ DNA synthesis Ⅲ heart regeneration C ardiomyocyte death with an ensuing loss of myocardial function is observed in many forms of cardiovascular disease. This progressive decline in cardiac function might be partially abated if the surviving myocardium retained even a limited ability to proliferate. Although it is generally accepted that adult cardiomyocytes retain some capacity to synthesize DNA, there is considerable debate regarding the frequency at which this occurs, and if reinitiation of DNA synthesis necessarily leads to cell division. 1,2 It is nonetheless clear that the intrinsic regenerative capacity of the adult mammalian heart is insufficient to restore cardiac function after significant injury. Consequently, considerable effort has been invested to study cardiomyocyte cell cycle regulation. 3 Cell cycle progression is regulated at multiple checkpoints to ensure that all requisite activities (ie, genome reduplication, DNA repair, and chromosome segregation) are completed before initiation of the next phase of the cell cycle. Checkpoint transit is regulated in part by a family of protein kinases (the cyclin-dependent kinases or CDKs) and their activating partners (the cyclins). For example, the initial commitment to a new round of cell division requires transit through the restriction point. Restriction point transit is regulated by CDK4 and the D-type cyclins. 4,5 CDK4/cyclin D-mediated phosphorylation of members of the RB protein family disrupts RB-E2F binding, thereby permitting E2F-mediated transcription of genes involved in regulating DNA synthesis. 6,7 Given the fundamental importance of restriction point transit in the activation of DNA synthesis and cell cycle progression, we have previously used the mouse ␣ cardiac myosin heavy chain (MHC) promoter to target expression of cyclin D1. 8 Cyclin D1 expression resulted in high rates of cardiomyocyte DNA synthesis in adult transgenic hearts, and was thus sufficient to drive cell cycle ...