Certain MicroRNAs Stimulate Regeneration of Adult Heart Tissue

Cardiac disease researchers working with a mouse model have discovered that by inducing a subset of microRNAs (miRNAs) that are active during development but silenced in the adult they could cause damaged adult heart tissue to regenerate.

The mammalian heart has limited capacity to regenerate after injury in part due to ineffective reactivation of cardiomyocyte proliferation. Investigators at the University of Pennsylvania (Philadelphia, USA) recently found that the microRNA cluster miR302-367 was important for cardiomyocyte proliferation during development and was sufficient to induce cardiomyocyte proliferation in the adult and promote cardiac regeneration. MiRNAs are fragments of RNA about 20 nucleotides long that block gene expression by attaching to molecules of messenger RNA (mRNA) in a fashion that prevents them from transmitting the protein synthesizing instructions they had received from the DNA.

The investigators reported in the March 18, 2015, online edition of the journal Science Translational Medicine that in their mouse model loss of miR302-367 led to decreased cardiomyocyte proliferation during development. In contrast, elevated miR302-367 expression led to a profound increase in cardiomyocyte proliferation, in part through repression of the Hippo signal transduction pathway. The Hippo signaling pathway controls organ size in animals through the regulation of cell proliferation and apoptosis. The pathway takes its name from one of its key signaling components, the protein kinase Hippo (Hpo). Mutations in this gene lead to tissue overgrowth, or a "hippopotamus"-like phenotype.

Induced expression of miR302-367 in adult animals reactivated the cell cycle in cardiomyocytes, resulting in reduced scar formation after experimental myocardial infarction. Furthermore, the number of heart muscle cells in these mice was found to increase. However, long-term expression of miR302-367 induced cardiomyocyte dedifferentiation and dysfunction, suggesting that persistent reactivation of the cell cycle in postnatal cardiomyocytes was not desirable. This limitation was overcome by transient systemic application of synthetic microRNAs that mimicked miR302-367, leading to increased cardiomyocyte proliferation and mass, decreased fibrosis, and improved function after injury.

"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," said senior author Dr. Edward E. Morrisey, professor of medicine and cell and developmental biology at the University of Pennsylvania. "This is a case of repressing a repressor."

"Persistent reactivation of the cell cycle in adult cardiomyocytes could be harmful and causes the heart to fail," said Dr. Morrisey. "We overcame this limitation by injecting synthetic microRNAs with a short half-life called mimics into the mice. The next stage in this study is to determine whether miRNA mimics will work in a larger animal model and to collaborate with bioengineers to create a local delivery system for the heart, rather than giving it systemically."

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