Researchers have discovered a novel approach to spur greater regeneration in heart tissue:
The heart tissue of mammals has limited capacity to regenerate after an injury such as a heart attack, in part due to the inability to reactivate a cardiac muscle cell and proliferation program. Recent studies have indicated a low level of cardiac muscle cell (cardiomyocyte) proliferation in adult mammals, but it is insufficient to repair damaged hearts. Researchers have now shown that a subset of RNA molecules, called microRNAs, is important for cardiomyocyte cell proliferation during development and is sufficient to induce proliferation in cardiomyocytes in the adult heart. MicroRNAs, which do not generate proteins, repress gene expression by binding messenger RNAs, which do generate proteins, and promote their degradation.
The loss of the microRNA cluster miR302-367 in mice led to decreased cardiomyocyte cell proliferation during development. In contrast, increased expression of the microRNA cluster in adult hearts led to a reactivation of proliferation in the normally non-reproducing adult cardiomyocytes. This reactivation occurred, in part, through repression of a pathway called Hippo that governs cell proliferation and organ size. "The Hippo pathway normally represses cell proliferation when it is turned on. The cluster miR302-367 targets three of the major kinase components in the Hippo pathway, reducing pathway activity, which allows cardiomyocytes to re-enter the cell cycle and begin to regrow heart muscle. This is a case of repressing a repressor."
In adult mice, re-expression of the microRNA cluster reactivated the cell cycle in cardiomyocytes, resulting in reduced scar formation after an experimental myocardial infarction injury was induced in the mice. There was also an increase in the number of heart muscle cells in these same mice. However, long-term expression of more than several months of the microRNA cluster caused heart muscle cells to de-differentiate and become less functional. The investigators surmised that cardiomyocytes likely need to de-differentiate to divide, but they may lose their ability to contract over time. "We overcame this limitation by injecting synthetic microRNAs with a short half-life called mimics into the mice." Mimic treatment for seven days after cardiac infarction led to the desired increase in cardiomyocyte proliferation and regrowth of new heart muscle, which resulted in decreased fibrosis and improved heart function after injury.