A new study showed that a cell-cycle regulator combination can induce cardiomyocyte proliferation and cell survival.
Myocardial infarction (MI or heart attack) is a result of decreased blood flow to heart tissue and heart tissue damage. The challenges in recovery from MI is due to the limited ability of regenerative processes within heart. The discovery of stem cells present in adult heart tissue has led to extensive research regarding their use for cardiac cell therapy. Some favorable effects of cardiac stem cell transplantation in injured cardiac tissue has been observed, but this may be due to processes unrelated to the growth of new cardiomyocytes.
Tools that unlock cell-cycle re-entry would provide a fascinating approach to regenerative medicine. A research group of a multi-university collaboration studied the ability of cell-cycle regulators to induce cell division in post-mitotic cardiomyocytes. Transition through phases of the cell cycle is regulated by specific complexes of cyclins and cyclin-dependent kinases. Therefore, combinations of these factors were studied using human cardiomyocytes in vitro and mouse heart tissue in vivo to determine the ability to induce cardiomyocyte proliferation and the effect on heart function.
The experimental approach involved the overexpression of specific cyclins (B1 and D1) and cyclin-dependent kinases (CDK1, CDK4) in mouse, rat, and human cardiomyocytes using an adenovirus vector. Overexpression of the combination in human cardiomyocytes derived from pluripotent stem cells resulted in cardiomyocyte proliferation. This was also observed in post-natal day 7 primary mouse cardiomyocytes and 4-month-old isolated adult rat cardiomyocytes. Cardiomyocyte division was tracked by lineage tracing in mice after intramyocardial injection of adenovirus encoding the cyclin/kinase combination. There was a 16% increase in cells compared to less than 1% in those injected with control virus.
Overexpression of the cyclin/kinase combination lead to signiﬁcant improvement in cardiac function after myocardial infarction. Using echocardiography and magnetic resonance imaging, it was found that the cell-cycle regulator combination improved ejection fraction, stroke volume, and cardiac output in mice. Overall, the tested cell-cycle regulator combination can induce cardiomyocyte proliferation and cell survival. Future studies can determine if a similar approach and regulators could enhance proliferation of other adult post-mitotic cell types throughout the body and bolster regenerative medicine efforts.
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Unlocking a cell's potential to regenerate the heart: Scientists identify genes that enable adult cells to divide and multiply. (2018). ScienceDaily. Retrieved 28 March 2018, from https://www.sciencedaily.com/releases/2018/03/180301125049.htm