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Induced Cardiomyocyte Proliferation
Spontaneous cardiomyocyte regeneration has been demonstrated in embryonic and neonatal mammals after genetic ablation, apical resection, or myocardial infarction. Adult cardiomyocyte proliferation and turnover have been reported to be minimal in human heartsand rodents. Cardiomyocyte division was also demonstrated to occur at a very low rate after acute and chronic infarction in humans.
Heart failure is the most prominent cause of hospitalization and one of the leading causes of mortality globally. During heart failure progression, damaged cardiomyocytes are replaced by fibrotic tissue, since cardiomyocytes are not able to regenerate themselves when damaged. This subsequently triggers cardiac remodeling and heart failure . All the current treatment strategies for heart failure are symptomatic treatments to slow down its progression. Hence, heart transplants, which are eminently scarce and not without complications, are as yet the only cure for heart failure .
2. Induction of Cardiomyocyte Cell Cycle Entry through Direct Cell Cycle Activation
Overexpression of cell cycle activators or knocking down of cell cycle inhibitors have been widely used to induce cardiomyocyte cell cycle entry. The cyclin D family and its related kinases (CDKs) are known to regulate the transition of the cell cycle from G1 to S phase, induce DNA synthesis, and maintain cell cycle activity . Cyclins A, D, and E, as well as the related kinases, are also involved in DNA synthesis, while cyclin B is crucial for cytokinesis . It has been shown that cyclin A and B disappear in adult hearts, while cyclin D, E, CDK2, and CDK4 expression and activity are very low in adult hearts .
Cyclin A2 is expressed during embryonic development of the heart and the early postnatal period and silenced afterward . Many studies have investigated the effect of cyclin A2 expression on cell cycle resumption. Chaudhry et al. showed cardiac enlargement with hyperplasia of cardiomyocytes in adult transgenic mice persistently expressing cyclin A2 . Woo et al. used an adenoviral vector to deliver cyclin A2 to mice hearts following left anterior descending (LAD) artery ligation. Cyclin A2-treated rats showed cardiac cell cycle activation associated with an improvement in hemodynamics, preload-adjusted maximal power, and cardiac output compared to control-treated rats . Similar findings were reported by Cheng et al. in cyclin A2 overexpression transgenic mice subjected to LAD artery ligation . Shapiro et al. confirmed these findings in large animals, namely pigs. Cyclin A2-treated pigs showed an ~18% increase in ejection fraction compared to control-treated pigs. Cultured porcine adult cardiomyocytes showed a more than threefold increase in the phospho-histone H3 (PHH3) in cyclin A2-expressing animals compared to controls .
Mohamed et al. showed efficient induction of stable cell cycle division, assessed by EdU and PHH3, in 15–20% of adult mouse, rat, and hiPS cardiomyocytes overexpressing a combination of four cell cycle genes; cyclin-dependent kinase 1 (CDK1), CDK4, cyclin B1, and cyclin D1 (termed 4F). Cell cycle induction using 4F also showed robust complete cytokinesis in vivo using MADM mice . In a trial for preclinical application of 4F, Abouleisa et al. cloned a polycistronic non-integrating lentivirus encoding 4F in which each factor was driven by TNNT2 promotor (TNNT2-4F-NIL) to induce cell cycling transiently and specifically in cardiomyocytes. Intramyocardial injection of TNNT2-4F-NIL improved systolic functions and reduced the scar size after ischemic reperfusion in rats and pigs compared to control-treated rats and pigs .
Another idea for the activation of cell cycle genes is to target cell cycle inhibitors. Sirt-1 is a member of the histone deacetylase (HDAC ) family, which deacetylate multiple targets including P21 protein. Hence, the deacetylated form of P21 is less stable and more prone to ubiquitination. Sirt-1 overexpression showed a significant reduction in active P21 acetylation, which resulted in a release of the inhibitory effect on the cell cycle genes and a significant increase in the mitotic markers, including PHH3 and Aurora B kinase-positive nuclei .
3. MicroRNA Regulates Cardiomyocyte Cell Cycle Entry
The miR-302-367 cluster is expressed in the early developmental stage in mouse hearts and it is involved in modulating cardiomyocyte proliferation during the embryonic stage. Expression of miR-302-367 led to continuous cardiomyocyte proliferation and reduction of scar size after MI, probably through inhibition of the Hippo signaling pathway. However, it also led to immature cardiomyocyte dedifferentiation and heart failure, while transient expression of miR-302-367 results in more controlled proliferation and does not deteriorate cardiac function .
miR-128 is a microRNA the upregulation of which coincides with cell cycle arrest. Neonatal mice overexpressing miR-128 showed impaired function and attenuated proliferation capacity, while miR-128 KO mice showed a prolonged postnatal proliferation window through suppressing CDK inhibitor p27 and activation of cell cycle regulator cyclin E and of CDK2. Adult KO mice showed improved scar size and cardiac function after MI . In this study, the authors suggested that the reduction in scar size was attributed to the dedifferentiation of the adult cardiomyocytes and their ability to proliferate, hence preventing the development of fibrosis.
miR-294 is another microRNA that is expressed during prenatal development and its expression is lost in adult cardiomyocytes. miR-294 expression in neonatal myocytes showed a significant increase in cell cycle markers Ki69, PHH3, and Aurora kinase-positive nuclei compared to control neonatal myocytes. miR-294–treated mice showed a significant improvement in scar size and apoptosis after MI compared to control mice. miR-294 increased cardiomyocyte proliferation through repression of Wee1 activity, which led to the activation of the cyclin B1/CDK1 complex .
Furthermore, another microRNA, miR-499 , has been found to regulate cardiomyocyte cell cycle entry and apoptosis via modulation of Sox6 and cyclin D1 activity .
4. Signaling Pathways That Control Cardiomyocyte Proliferation
The entry is from 10.3390/ijms22147720
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