Institution Spotlight: Cardiomyocyte regeneration research a focus at Penn Medicine

One of the most significant recent developments in cardiac research at Penn Medicine was achieved by mimicking the regeneration mechanisms of fish and frogs.

"A question that we have been asking for some time is how we can get the mammalian heart — the human heart in particular — to repair itself, since it doesn’t do it that well,” Ed Morrisey, PhD, professor of medicine, professor of cell and developmental biology, and scientific director of the Institute for Regenerative Medicine in the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, told Cardiology Today. “We started out with the idea that lower animals — for example, zebrafish — can do this quite readily.”

Ed Morrisey

Cardiology Today about the heart muscle repair mechanisms of lower species, and how University of Pennsylvania researchers are incorporating these adaptations into human myocardial muscle regeneration.

Question: How do the hearts of lower animals respond differently to cardiac injury than the hearts of humans or other mammals?

Answer: In lower animals, the heart adapts differently to injury by increasing proliferation in cardiac muscle cells or cardiomyocytes. Previous research has indicated that proliferation of these cardiomyocytes may be promoted by microRNAs, a subset of RNA molecules that are not expressed in the adult mammalian heart.

The idea is that different cell types respond differently in the human or mouse heart vs. a lower animal such as a zebrafish or frog. If you have an acute injury like MI in a high-pressure system, this could lead to rupture resulting in a rapid loss of blood. Therefore, the rapid generation of a scar to maintain stability of the tissue is important. In contrast, in a simpler system, like the zebrafish or the frog, where the circulatory system is a low-pressure system, there is less pressure to rapidly form a rigid scar to prevent blood loss. This allows the time for proper regeneration of cardiomyocytes and reestablishment of cardiac muscle tissue.

Question: In your research, you have investigated inducing cardiomyocyte proliferation in the mouse heart through re-expression of certain microRNA clusters. What are your main findings so far?

Answer: Yes, one of our main questions in the lab is how to induce cardiomyocyte proliferation in the adult mouse heart. During development, the loss of the microRNA cluster miR302-367 decreased the proliferation of cardiomyocyte cells. Conversely, in adult mouse hearts, increased expression of this microRNA cluster led to reactivation of cardiomyocyte proliferation. This was partly mediated by repression of the Hippo pathway, which regulates cell proliferation and organ size.

When MI was induced in the mice, re-expression of the microRNA cluster reactivated the cell cycle in cardiomyocytes, leading to decreased scar formation and an increase in the number of cardiomyocytes in the mice.

Long-term expression of the microRNA cluster, however, led to de-differentiation of heart muscle cells and a decrease in function. When this happened, the hearts began to fail and exhibit classic signs of human heart failure. To circumvent that problem, we treated mice with a small molecule version of the miRNAs called mimics for a short period of time after injury. MicroRNA mimics are essentially just a processed microRNA and they can be injected systematically into the bloodstream.

Over 7 days of treatment with injectable, synthetic microRNA mimics, we were able to achieve optimal increases in cardiomyocyte proliferation in the mice, leading to growth of new heart muscle, decreased fibrosis and improvements of heart function after MI.

Question: How do you hope to use these findings for human MI recovery, and what is the potential timeline for doing so?

Answer: While these studies are still in their early stages, the possible implications for human heart function are fairly straightforward: If we can activate cardiomyocyte proliferation and regrowth of heart muscle after MI using microRNA mimics or other related methods, clinicians may be able to prompt the heart to repair itself, without leading to loss of cardiac function over time. Ultimately, this is what we hope to achieve. The goal is to investigate this approach in larger animal models, and develop a local delivery system to the heart.

In addition, microRNAs are being investigated at many levels and for various applications. There are other microRNAs that are being used for therapeutic approaches in humans; clinical trials are ongoing for those right now. So one could imagine that this could be ramped up to clinical trials, but it will still be probably 5 to 10 years down the road. – by Jennifer Byrne

Disclosure: Morrisey reports no relevant financial disclosures.