Evidence That Human Cardiac Myocytes Divide after Myocardial Infarction (original) (raw)
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Myocyte growth in the failing heart
Surgical Clinics of North America, 2004
Adult ventricular myocytes can undergo mitotic division, resulting in an increase in the aggregate number of cells in the heart. The improvement in the methodological approach to the analysis of tissue sections by immunostaining and confocal microscopy has defeated the dogma that myocyte regeneration cannot occur in the adult heart. Most importantly, primitive and progenitor cells have been identified in the human heart. These cells express telomerase and have the capability of undergoing lineage commitment and rapid cell division, expanding significantly the contracting ventricular myocardium. These cell populations possess all the molecular components regulating the entry and progression through the cell cycle, karyokinesis, and cytokinesis. The recognition that myocyte hypertrophy and regeneration, as well as myocyte necrosis and apoptosis, occur in cardiac diseases has contributed to enhancing our understanding of the plasticity of the human heart.
Dividing cardiomyocytes are observed in autopsied human hearts following recent myocardial infarction, however there is a lack of information in the literature on the division of these cells. In this study we used a rat model to investigate how and when adult mammalian cardiomyocytes proliferate by cell division after myocardial infarction. Myocardial infarction was induced in Wistar rats by ligation of the left coronary artery. The rats were sacrificed periodically up to 28 days following induced myocardial infarction, and the hearts subjected to microscopic investigation. Cardiomyocytes entering the cell cycle were assayed by observation of nuclear morphology and measuring expression of Ki-67, a proliferating cell marker. Ki-67 positive cardiomyocytes and dividing nuclei were observed initially after 1 day. After 2 days dividing cells gradually increased in number at the ischemic border zone, reaching a peak increase of 1.12% after 3 days, then gradually decreasing in number. Dividing nuclei increased at the ischemic border zone after 3 days, peaked by 0.14% at day 5, and then decreased. In contrast, Ki-67 positive cells and dividing nuclei were limited in number in the non-ischemic area throughout all experiments. In conclusion, mitogenic cardiomyocytes are present in the adult rat heart following myocardial infarction, but were spatially and temporally restricted. (Mol Cell Biochem 259: 177–181, 2004)
Acute myocardial infarction induced functional cardiomyocytes to re-enter the cell cycle
American journal of translational research, 2013
Loss of cardiomyocytes after myocardial infarction (MI) causes heart failure. In this study, we investigate whether the in situ cardiomyocytes can re-enter the cell cycle and to what extent cell division of cardiomyocytes occurs after acute MI (AMI) in rats. Sprague Dawley (SD) rats were used in this study; the left anterior descending coronary artery was ligated. At time points (3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks) after the operation, five rats were euthanized, respectively. An additional five sham-operated rats serves as a control group and were euthanized at 3 days post-operation. The expressions of cyclin A2, Ki-67, phospho-histone H3 (H3P), and Aurora B in myocardial tissues were detected by Western blot and immunofluorescence. The expression levels of cyclin A2 were significantly higher in all groups with AMI except the 4-week group than those found in the sham-operated group (P < 0.01). The percentage of Ki-67-positive nuclei in the border zones was significantl...
Nadal-Ginard et al Myocyte Death and Growth in the Diseased Heart
2003
The accepted paradigm considers the adult mammalian heart as a postmitotic organ, which possesses a relatively constant number of myocytes from shortly after birth to adulthood and senescence. This notion is questioned by the demonstration that although most adult myocytes are terminally differentiated, there is a small and continuously renewed subpopulation of cycling myocytes produced by the differentiation of cardiac stem-like cells. Myocyte death and myocyte regeneration are introduced as major determinants of cardiac homeostasis and alterations of ventricular anatomy and function in physiological and pathological states. The possibility of reconstituting dead myocardium by stem-like cells is advanced and proposed as a major area of future research. (Circ Res. 2003;92:139-150.)
Myocyte renewal and ventricular remodelling
Nature, 2002
insight progress 240 NATURE | VOL 415 | 10 JANUARY 2002 | www.nature.com C ardiac myocytes are thought to be terminally differentiated cells and have been often compared to neurons for their inability to regenerate and replace damaged myocardium. Even though evidence now exists for adult neurogenesis and neural stem cells 1 , the concept of myocyte regeneration has not been embraced by the medical community and remains highly disputed 2 . Hypertrophy has been assumed to be the only form of myocyte growth in the heart, and over the years information has been gathered on the many signalling pathways implicated in myocyte hypertrophy 3 . Conversely, the mechanisms of myocyte regeneration have been mostly neglected.
Cardiovascular Research, 2005
Objective: Although the genetic program for reinitiating DNA synthesis exists in post-mitotic cardiomyocytes, and it was reported that in human acute myocardial infarction (AMI) a significant proportion of myocytes enter mitosis, the rule is that the lost tissue is replaced by a collagen scar. The purpose of this study was to search for the basis of this discordance in order to devise future strategies to induce division of myocytes into daughter cells that may replace the lost tissue with contractile cells. Methods: In 15 human hearts with 1-to 21-day-old infarcts, the expression of the cell cycle proteins Ki67 antigen, cyclins D, A, and B1, the presence of mitotic bodies, and the ploidy status were investigated with immunoenzymatic methods, light and laser confocal microscopy, and densitometry in the myocytes surrounding the infarct area. Results: In 7-to 13-day-old infarcts, 11.61 F 6.94% of the myocytes presented Ki67+ nuclei, and a lower proportion presented cyclins D, A, and B. At earlier and later times, the proportion of Ki67+ myocytes was significantly lower. Although under confocal microscopy and fluorescent labels, some of the Ki67+ myocytes appeared to be in different stages of mitosis, with Nomarski optics and hematoxylin counterstaining, the condensed chromosomes, although arranged in metaphase and anaphase plates or split in sister chromatids, were always located within a preserved nuclear envelope, indicating the presence of endomitosis. Conventional mitosis was exceptionally observed. In the 14-and 21-day-old infarcts, the ploidy of the myocytes adjacent to the infarct was significantly higher than in distant zones. Conclusion: These observations indicate that in human infarcts, entrance of cardiomyocytes into the cell cycle is transient and that endomitosis, leading to polyploidy, rather than mitosis, leading to karyokinesis, is the final fate of cycling cells. Both observations may account for the discordance between the regenerative ability of myocytes and the lack of an efficient reparative process in human AMI.
Myocyte Death, Growth, and Regeneration in Cardiac Hypertrophy and Failure
2000
Abstract—The accepted paradigm considers the adult mammalian heart as a postmitotic organ, which possesses a relatively constant number,of myocytes,from shortly after birth to adulthood and senescence. This notion is questioned by the demonstration that although most adult myocytes are terminally differentiated, there is a small and continuously renewed,subpopulation of cycling myocytes,produced by the differentiation of cardiac stem-like cells. Myocyte death