More Evidence for Hippo Pathway Blockade to be a Road to Enhanced Regeneration

In the research I'll point out today, scientists interfere with the Hippo signaling pathway in mouse heart tissue to spur greater regeneration following a heart attack. The pathway controls cell proliferation, making it the target of attention from the regenerative medicine research community. Today's paper is one of a number of approaches that target this pathway: a fair few groups are involved in work on enhanced regeneration that in some way touches upon Hippo activity. When looking back at a sampling of the past few years, there are studies using microRNAs to interdict one part of the pathway, others uncovering regulatory RNAs that adjust this complex machinery at a different point, work on mapping links between Hippo and other pathways known to be involved in regeneration, and a paper reporting that suppression of the Hippo pathway makes the liver more regenerative by allowing mature cells to dedifferentiate into progenitor cells.

It is not unreasonable to expect there to be manipulations that enhance regeneration. Evolution doesn't optimize for individual convenience. There are many fairly similar species with broadly different regenerative capacities that evolved from a common ancestor. Somewhere there must be changes of a comparatively modest scope that change the degree to which tissues maintain themselves. "Modest scope" in the context of cellular biochemistry may still be ferociously complex as an implementation project for medical technology, but the examples found to date are promising, even taking into account the potential risk that any specific approach to producing increased regenerative activities may significantly increase the risk of cancer.

Beyond stem cell therapies and the machinery surrounding the Hippo pathway, we can also point to adjustment of macrophage polarization and levels of cellular senescence as ways to improve baseline human regeneration or reverse some of the declines that take place with age. As an aside on that latter topic, one can draw links between cellular senescence and Hippo pathway activity, and given the recent understanding that senescent cells disrupt regeneration and are a significant cause of fibrosis, it is very interesting to see that the researchers here find that disabling Hippo pathway activity reduces fibrosis following injury in the heart. Researchers are also narrowing down some of the important differences between mammals that cannot regrow limbs and species such as salamanders and zebrafish that can. It is a little early to say where this will all end up a decade or two from now, but the advent of multiple methods of incrementally improving regenerative capacity for short period of time, so as to evade increased cancer risk, seems a safe prediction.

Scientists reverse advanced heart failure in an animal model

Researchers have discovered a previously unrecognized healing capacity of the heart. In a mouse model, they were able to reverse severe heart failure by silencing the activity of Hippo, a signaling pathway that can prevent the regeneration of heart muscle. During a heart attack, blood stops flowing into the heart; starved for oxygen, part of the heart muscle dies. The heart muscle does not regenerate; instead it replaces dead tissue with scars made of cells called fibroblasts that do not help the heart pump. The heart progressively weakens; most people who had a severe heart attack will develop heart failure.

"One of the interests of my lab is to develop ways to heal heart muscle by studying pathways involved in heart development and regeneration. In this study, we investigated the Hippo pathway, which is known from my lab's previous studies to prevent adult heart muscle cell proliferation and regeneration. When patients are in heart failure there is an increase in the activity of the Hippo pathway. This led us to think that if we could turn Hippo off, then we might be able to induce improvement in heart function."

"We designed a mouse model to mimic the human condition of advanced heart failure. Once we reproduced a severe stage of injury in the mouse heart, we inhibited the Hippo pathway. After six weeks we observed that the injured hearts had recovered their pumping function to the level of the control, healthy hearts." The researchers think the effect of turning Hippo off is two-fold. On one side, it induces heart muscle cells to proliferate and survive in the injured heart, and on the other side, it induces an alteration of the fibrosis. Further studies are going to be needed to elucidate the changes observed in fibrosis.

Hippo pathway deficiency reverses systolic heart failure after infarction

Mammalian organs vary widely in regenerative capacity. Poorly regenerative organs such as the heart are particularly vulnerable to organ failure. Once established, heart failure commonly results in mortality. The Hippo pathway, a kinase cascade that prevents adult cardiomyocyte proliferation and regeneration, is upregulated in human heart failure. Here we show that deletion of the Hippo pathway component Salvador (Salv) in mouse hearts with established ischaemic heart failure after myocardial infarction induces a reparative genetic program with increased scar border vascularity, reduced fibrosis, and recovery of pumping function compared with controls.

Using translating ribosomal affinity purification, we isolate cardiomyocyte-specific translating messenger RNA. Hippo-deficient cardiomyocytes have increased expression of proliferative genes and stress response genes, such as the mitochondrial quality control gene, Park2. Genetic studies indicate that Park2 is essential for heart repair, suggesting a requirement for mitochondrial quality control in regenerating myocardium. Gene therapy with a virus encoding Salv short hairpin RNA improves heart function when delivered at the time of infarct or after ischaemic heart failure following myocardial infarction was established. Our findings indicate that the failing heart has a previously unrecognized reparative capacity involving more than cardiomyocyte renewal.


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