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Cardiomyocyte Cell Cycle Regulation Kishore B.

S. Pasumarthi, Loren J. Field 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. (Circ Res. 2002;

90:1044-1054.) Key Words: cardiomyocyte proliferation Ⅲ cardiac myocyte apoptosis Ⅲ heart regeneration Ⅲ gene targeting Ⅲ transgenic mice Studies 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.1C3 On migration, these cells proliferate extensively4 while re- maining in close contact with the anterior endoderm3 (a prerequisite for their subsequent cardiomyogenic induction).5 Recent studies have elegantly identified several growth fac- tors 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 chor- din).6C9 The failure of these growth factors to promote cardiomyogenic induction in more primitive precursor cells indicates that additional as of yet unidentified factors partic- ipate in the process. In contrast to our somewhat limited understanding of the inductive clues that mediate cardiomyogenic lineage deter- mination, 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 dorsal side becoming the inner curvature.13 These outer and inner curvatures play critical roles in the morphogenesis of the 4-chambered heart, as the individual chambers balloon out from the outer curvature due to the rapid proliferation of resident myocardial cells. These mor- phogenic changes are accompanied by the expression of chamber-specific genes exclusively in the ventral side and the outer curvature of the heart tube. In contrast, myocardial cells residing in the inner curvature are thought to be relatively undifferentiated, which allows this region to participate in the alignment of the right atrium with the right ventricle and the left ventricle with the outflow tract. This process results in the separation of the pulmonary and systemic circulations.13 Gene-targeting experiments have identified a number of transcription factors that are required for cardiac develop- ment, morphogenesis, and/or chamber specification. These include members of Nkx,14 GATA,15,16 MEF2,17 HAND,18,19 Irx,20 Tbx,21 and HRT22 families of transcription factors. Cardiomyocyte Cell Cycle Regulation During Development Cell cycle activity is an intrinsic component of cardiac differentia- tion and morphogenesis, as evidenced by traditional tritiated thymi- dine incorporation studies. An exceedingly high level of DNA synthesis (labeling indices approaching 70%) is seen in the precar- diac mesoderm of the myoepicardial plate in E8 mouse embry- Original received January 22, 2002;