Guest post: Dr. Gabriele D’Uva: How to Grow New Heart Cells

Dr. Gabriele D'Uva is finishing up his postdoctoral research at the Weizmann Institute. Here is his account of three years of highly successful research on regenerating heart cells after injury. Among other things, it is the story of the way that different ideas from vastly different research areas can, over the dinner table or in casual conversation, provide the inspiration for outstanding research:Gabriele

Three years ago, when I joined the lab of Prof. Eldad Tzahor, the emerging field of cardiac regeneration was totally obscure to me. My scientific track at that time was mainly focused on normal and cancer stem cells: cells that build our bodies during development and adulthood.  The deregulation of these cells can lead to cancer. I have to admit that I didn’t know even the shape of a cardiac cell when my postdoc journey started…

Eldad’s lab was also switching fields -- well, not drastically, like me, but still it was a transition from a basic research on the development of the heart to the challenge of heart regeneration during adult life.

 

Two neonatal cardiomyocytes (staining in red) undergoing cell division after treatment with NRG1

In contrast to most tissues in our body, which renew themselves throughout life using our pools of stem cells, the renewal of heart cells in adulthood is extremely low; it almost doesn’t exist. Just to give an approximate picture of renewal and regeneration processes: Every day we produce billions of new blood cells that completely replace the old ones in a few months. In contrast, heart cells renewal is so low that, many cardiac cells remain with us for our entire life, from birth to death! Consequently, heart injuries cannot be truly repaired, leading to (often lethal) cardiovascular diseases. This might appear somewhat nonsensical, since the heart is our most vital organ: No (heart) “beat” no life.

 

Hence a challenge for many scientists is to understand how to induce heart regeneration Scientists have been trying different strategies, for example, the injection of stem cells. We decided to adopt a different strategy – one that mimics the natural regenerative process of healing the heart in such “regenerative” organisms as amphibians and fish, and even newly-born mice. In all these cases the regeneration of the heart involves the proliferation of heart muscle cells called cardiomyocytes. Therefore the challenge before us was: “How can we push cardiomyocytes to divide?”

We adopted a team strategy. Cancer turned out to be a somewhat useful model for a “strategy.” After all, the hallmark of this disease is continuous self-renewal and cell proliferation. Starting from this thought, Prof. Yossi Yarden, a leading expert in the cancer field, suggested: “Why don’t you try an oncogene, such as ERBB2, whose deregulation can lead to uncontrolled cellular growth and tumour development?” The idea was that cardiomyocytes could be pushed into a proliferative state by this cancer-promoting agent. To Eldad, this was a nice “life” circle closing, since Eldad, when he was a PhD student in Yossi’s lab, focused exactly on the ERBB2 mechanism of action in cancer progression. I must admit, the idea sounded very intriguing and I really liked it.

Eldad, as a developmental biologist, had a different approach. Based on his field of expertise, his tactic was to apply proliferative (and regenerative) strategies learned from the embryos, when heart cells normally proliferate to form a functional organ. It turned out that a key player in driving embryonic heart growth is again… ERBB2!

So, Yossi and Eldad, from different fields of expertise, had the same idea: Look to ERBB2, which is a receptor on the cell surface that amplifies and transmits growth factor signals. It looked, back then, like a challenging idea; I was very happy to take the dare.

So this is exactly how my three and half years of post doc research started. At that stage, ERBB2 looked like a perfect candidate for cardiac regeneration. The idea to bring together cancer and developmental knowledge doubled the percentage of our success. The odds were on my side!

A first rule to starting a project regarding the role of any protein is to check for its expression. Therefore I started to analyse the kinetic of expression of ERBB2 in a normal heart during post-natal development. Interestingly, I noticed a dramatic reduction in ERBB2 levels in the heart during the first week of post-natal life. I have to mention that mouse cardiomyocytes stop dividing soon after birth, in about a week. It’s probably a residual proliferative ability of their embryonic life. My initial results revealed a strong reduction in ERBB2 expression, exactly coincident with the period in which heart cells lose their proliferative and regenerative capabilities.

I was very intrigued by this result, which immediately opened a very important question: “Is the loss of the regenerative ability of the heart in mice due to the decline of ERBB2 expression after birth?” After hundreds of experiments I can confidently answer: Yes. ERBB2 levels are reduced in cardiomyocytes shortly after birth, and this down-regulation limits the proliferative and regenerative ability of cardiac muscle cells.

To prove that, we first generated mice in which we deleted the Erbb2 gene specifically in heart cells. Loss of the ERBB2 gene (and protein) led to reduced cardiomyocyte proliferation and consequently to a very thin and poorly contracting heart. In the absence of ERBB2, the heart at birth was so weak that it could not tolerate the blood pressure and became dilated, a cardiac disease in humans known as dilated cardiomyopathy. The conclusion was that EBB22 is required for proper proliferation and growth of heart during embryonic development and its expression is physiologically reduced soon after birth to allow maturation of the cardiomyocytes.

Cardiomegaly (giant heart) in adult mice upon induction of Erbb2 (heart on the right) compared to normal mice (heart on the left) Cardiomegaly (giant heart) in adult mice upon induction of Erbb2 (heart on the right) compared to normal mice (heart on the left)

Because of its major role in cancer, the only way to study ERBB2 involvement during heart regeneration was to search for a sophisticated system to finely, and transiently, increase its levels in the heart, within defined time windows. For this, we generated mice in which we could switch ERBB2 ON or OFF in cardiomyocytes. The results were amazing. Persistent ERBB2 induction led to a giant heart, two to three times bigger than normal in just a week or two. The analysis of the mechanism demonstrated that ERBB2 gets muscle cell to “rejuvenate” to an earlier stage (a phenomenon called “dedifferentiation”) and to reacquire the ability to proliferate -- similar to what happens during embryonic development. In addition, ERBB2 increases the size of the cardiomyocytes (a phenomenon called “hypertrophy”).

Thus far, the project had been proceeding in the right direction. However we soon realized that a bigger team could improve the project’s success. A very talented master’s student, Alla Aharonov, joined me in this effort. Alla’s help was precious in many ways. In particular, she contributed to our resolving the specific molecular pathways that are mediated by ERBB2 activation. Precious help in the analyses of cardiac functions were obtained from the lab of Profs. Jonathan Leor and Michal Neeman. Very important were also the “dinner discussions” with my wife, Mattia Lauriola (who was conducting a parallel postdoc in Yossi Yarden’s lab), in addition to Yossi’s scientific support and help from the beginning of the project. At certain point Eldad also involved Prof. Richard Harvey, a good friend of his and a leading scientist in heart development, whose suggestions turned out to be very effective. The project and the team were blooming.

The main findings, which we are happy to report, are that transient activation of ERBB2 (ranging from 10 days to 3 weeks) can trigger cardiomyocyte dedifferentiation and proliferation. These two processes in turn are critical to achieving cardiac regeneration after the injury that we had induced in mice to mimic human heart attacks. (termed myocardial infarction). Therefore, the activation of ERBB2 is one strategy to promote heart regeneration. It’s important to mention that one of the therapies currently being tested in clinical trials is a growth factor stimulus called Neuregulin1 (NRG1), which activates ERBB2 signalling. However, since we uncovered the fact that that ERBB2 levels are very low in adult mouse cardiomyocytes, we suggest that the efficacy of NRG1 therapy might be limited in adulthood. Further experiments in cardiomyocytes derived from human patients could answer this question.

The good news is that, according to our results, heart patients will definitely improve if we can, in the future, find a way to fine-tune ERBB2 levels. We need to find a way to control the expression of this receptor, or its signalling partners, for a short time to repair the damaged heart. How? That’s the next challenge; but it which could help millions patients worldwide!

 Our findings point to a central role of ERBB2 in cardiomyocyte cell division and regeneration.

 

 

 

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This was such an interesting read! I am amazed by the continuous progress being made under the radar. Is it possible to manipulate the heart from birth to ensure that levels of ERBB2 never decrease? I am looking forward to see how these results will alter the treatment of heart conditions.

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By Estie-Lome' Mouton (not verified) on 13 Apr 2015 #permalink

What are the chances of succeeding in finding a way to fine-tune ERBB2 levels and a way to control the expression of this receptor, or its signalling partners, for a short time to repair the damaged heart in the future?and is it guaranteed that when you succeed in these findings heart patients will improve?

By Matanhire Mich… (not verified) on 13 Apr 2015 #permalink

Wow that is amazing! More research should definitely be done on the subject. I am confident that these findings will help to ensure that heart diseases will be treated easily and that people with weak hearts will have a chance to live a normal life. (15001548)

By Antoinette van Wyk (not verified) on 13 Apr 2015 #permalink

what is the difference between cardiac and tissue cell that give rise the high frequent renewal of the tissue cells but extremely low to the cardiac cell?

By Sifiso Dubazan… (not verified) on 13 Apr 2015 #permalink

That is excelent work indeed.I claim with no doubt that these findings can extend to other interesting researches about the heart.

By Boysana Ramalo… (not verified) on 13 Apr 2015 #permalink

I find this research ground-breaking and indicates that science is one step closer to finding the life-saving therapy and treatment that patients with cardiovascular disease need. It is enlightening to also know how heart cell stop regenerating from birth which highlights the importance not taking one's heart health for granted. It would be great if similar research can be done on the regeneration of neuron cells in the body which like this research, will cure other various degenerative diseases.

By Refiloe Motsatsi (not verified) on 13 Apr 2015 #permalink

I find this research very remarkable and proves that science is one step closer to finding a cure for patients suffering from various cardiovascular diseases. Can the same approach be used to treat other damaged tissues such as the in the brain when a patient has suffered a stroke?

By Refiloe Motsatsi (not verified) on 13 Apr 2015 #permalink

It is incredible to turn something negative into something positive. Can the same cancer growth idea be used for other organs as well? I would love to see how this idea can be used in the brain or nervous system to cure auto immune degenerative diseases. It is unbelievable to imagine where the medical research will be in 20 years from now. The life expectancy can increase drastically.

By Danielle van Wyk (not verified) on 14 Apr 2015 #permalink

with such groundbreaking studies it would now seem that soon the world would be populated by older and older people. Is there no possible way of programming the heart cells to function like those of the liver?

By Damean Billson (not verified) on 14 Apr 2015 #permalink

i would pose the same question as you danielle, can it also be used for other organs? so that finally we can get a cure for cancer not a guarantee of losing a loved as soon as they have cancer, this would help a lot of people in different ways.Excelent work being down by our scientist and physicians

By u14241308 M Ma… (not verified) on 15 Apr 2015 #permalink

excellent work being done by our scientist and physicians i meant

By u14241308 M Ma… (not verified) on 15 Apr 2015 #permalink

The fact that this discovery has been made could have unlimited possibilities! would it be possible to synthesize ERBB2 that is might be possible in humans to utilize it when it is needed, for example in patients with failing hearts? Or perhaps a way unto which the production of ERBB2 could be increased to an extent that humans continue to produce it only to regenerate heart cells without the side effect of an enlarged heart as seen by the mouse heart three times the size of a normal mouse heart. Very interesting read though and cannot wait for further advancements in this field. u15016677

By Theo Hohls (not verified) on 15 Apr 2015 #permalink

If these ERBB2 cells are known to stimulate growth, could it not also be used in other areas of the body where for example there is a cell deficiency, or maybe with diabetes where there is a low production of the necessary components. There should be a way to use ERBB2 in other areas of the body as well.

By Marcelle de Jong (not verified) on 15 Apr 2015 #permalink

I find this research very interesting, I can even see myself doing perhaps something similar in the future. This research not only have the potential to change the way we look at the human heart but also the way we look at various degenerative diseases. It will change the medical world drastically. One thing I am wondering about is why the heart has such a low renewal rate?

By Adam Boyens (not verified) on 15 Apr 2015 #permalink

Well done on the research conducted and progress made in the field of cardiac regeneration. It truly made for a very informative read and it was interesting to note about the almost non-existing renewal of heart cells. The research provides hope that damaged hearts could be repaired in the near future. Keep up the good work! (04648685)

It is amazing! More research ought to certainly be done on the subject. I am certain that these discoveries will help to guarantee that heart sicknesses will be dealt with effectively and that individuals with frail hearts will have an opportunity to carry on with a typical life

By dr Nadim M. Za… (not verified) on 16 Apr 2015 #permalink

This is amazing, to think that researchers has come this far in a matter of a few years. The regeneration of heart cells is maybe one of the most important medical fields to explore to ensure that people with heart damage can live a full life despite their condition.
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By Charne Coetzer (not verified) on 16 Apr 2015 #permalink

Since ERBB2 seems to be triggered in all the cardiac tissue, leading to hypertrophy, which in itself is potentially fatal, how would one limit its action or generation to specific areas affected by myocardial infarction, which are necrotic? Put another way, how would one achieve a patch effect?

By Marnel (u15008160) (not verified) on 17 Apr 2015 #permalink

This research is so inspirational and very interesting. I can't wait to see how damaged hearts will be repaired in the future. It is amazing how medical science has improved.

By Carike Odendaa… (not verified) on 17 Apr 2015 #permalink

Well done to medical science! It is amazing how the world of medicine has improved.

This is very interesting. I can not wait to see how damaged heart will be repaired in the future. This is outstanding work done by scientists and physicians. Science just keep improving our lives day by day.

By Carike Odendaa… (not verified) on 18 Apr 2015 #permalink

I found this article not only interesting but inspiring, To take the concept and idea of what cancer does to the cell, then to apply it to an organ where regenerative capabilities are needed?. My only question is are we able to control ERBB2 receptors and the growth of the heart cells? and as asked in comment #8 can this be applied to other internal organs??

By Jaclyn Moneron… (not verified) on 18 Apr 2015 #permalink

What are the chances of cardiac regeneration in baby's born with holes in their hearts,especially baby's born with down syndrome? Will this research project be of any help to them?

By ZG Manzini (u1… (not verified) on 18 Apr 2015 #permalink

This is truly fascinating. I had no idea that heart cells could not be renewed or repaired. An interesting point to acknowledge however is why try to repair an organ that is destined to fail at some point? Why not replace the organ with a more reliable, longer lasting piece of equipment? I believe further studies should be focused on cybertronics.
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I'm really impressed with this research and hope to one day partake in this exciting search to cure the heart!!!

WOW hopefully by the time my heart gives in this research would have been completed and my heart saved ;)

To all you South African commenters: sorry if your comments did not appear immediately. I was on vacation, but tried to get them up as soon as I could.

Please keep up your interest in this site and in science!