Adult mouse heart after activation of both proteins vital for cell replication. Green shows cells replicating. [Dr Cathy Wilson, University of Cambridge]

The results of studies in mice suggest that triggering a cancer-related gene to function in normally unresponsive heart cells prompts cell proliferation and could offer a new approach to regenerating heart tissue damaged by heart disease. Since adult hearts cannot usually repair themselves once damaged, harnessing the power of this gene represents major progress towards the first curative treatment for heart disease.

“This is really exciting because scientists have been trying to make heart cells proliferate for a long time,” said Catherine Wilson, PhD, a researcher at the University of Cambridge department of pharmacology, who led the study. “None of the current heart disease treatments are able to reverse degeneration of the heart tissue—they only slow progression of the disease. Now we’ve found a way to do it in a mouse model.” The University of Cambridge team, working with scientists in Australia and Italy, reported on their studies in Nature Communications, in a paper titled, “Reactivation of Myc transcription in the mouse unlocks its proliferative capacity.”

Heart failure affects around 23 million people worldwide each year, and there is currently no cure. An adult human heart can lose up to one billion heart muscle cells as a result of a heart attack. Unlike many other organs in the body, the adult heart can’t regenerate itself, so the cells are never replaced. Their loss reduces the strength of the heart and can cause scar formation, heart failure, and ultimately death.

The cell cycle is tightly controlled in mammalian cells, and cancer develops when cells start to replicate uncontrollably. The transcription factor Myc is widely acknowledged to play a pivotal coordinating role in the transcriptional control of how body cells normally proliferate and tissues regenerate, the authors explained. An analysis of Myc activity in different cell types indicates that it ultimately regulates the expression of thousands of genes, “perhaps a third of the transcriptome,” the authors explained. However, Myc also plays a key role in the process by which cells start to replicate uncontrollably in cancer, and the protein is known to be overactive in the vast majority of cancers.

Given its prominent role in cancer, considerable research has focused on understanding how different tissues respond to Myc, and potentially taking control of Myc as an approach to cancer therapy. “Since deregulated and elevated Myc expression is a pervasive and causal attribute of most, perhaps all, tumors, understanding how tissue-specific responses to Myc are determined at a molecular level is imperative,” the researchers wrote.

Not all tissues respond in the same way to Myc, and the heart is refractory to the gene’s mitogenic effects, the authors pointed out. When the researchers made Myc overactive in a mouse model, the cancerous effects of the gene were evident in multiple organs including the liver and lungs, in which huge numbers of cells started replicating over the course of a few days. But there was no such response in the heart.

Further investigation indicated that Myc-driven activity in heart muscle cells is critically dependent on the level of another protein, Cyclin T1, which is the product of the gene Ccnt1. The team’s experiments showed that when the Ccnt1 and Myc genes are expressed together, the heart switches into a regenerative state and its cells start to replicate. “When these two genes were overexpressed together in the heart muscle cells of adult mice we saw extensive cell replication, leading to a large increase in the number of heart muscle cells,” said Wilson.

Using ChIP next generation sequencing the researchers were able to follow the action of Myc in the heart cells. The Myc transcription factor normally binds to DNA in specific cells and activates gene expression. But in the heart cells, while the protein did bind successfully, the cells didn’t start to replicate because the protein could not activate gene expression. The other protein vital to gene expression, Cyclin T1, was deficient in the heart. The team showed that adding Cyclin T1 to the cells in parallel with overactive Myc caused the cells to start proliferating.

“Overall, our data indicate that tissue regenerative capacity is tightly linked to the capacity of that tissue to respond to Myc and that tissue Myc responsiveness is governed principally by availability of key components of the core transcriptional machinery, which Myc co-opts to drive its regenerative biological output,” the authors noted. “However, in addition to its core target genes, which are common across tissues, a significant number of its targets are expressed in a tissue-specific manner. By contrast, tissue-specific accessibility of target genes to Myc appears to be dictated principally by hard-wired, tissue-specific epigenome organization.”

Wilson commented, “None of the current treatment options can reverse the degeneration of heart tissue. The inability of the heart to regenerate itself is a significant unmet clinical need. We found that even when Myc is switched on in a heart, the other tools aren’t there to make it work, which may be one of the reasons heart cancer is so extremely rare. Now we know what’s missing, we can add it and make the cells replicate.”

The researchers hope to use their findings as the basis for developing a genetic therapy for heart disease. “We want to use short-term, switchable technologies to turn on Myc and Cyclin T1 in the heart,” Wilson noted. “That way we won’t leave any genetic footprint that might inadvertently lead to cancer formation.” The investigators suggest that their findings could also offer up more general insights into regenerative medicine and cancer susceptibility.

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