How does the heart regenerate? After countless brainstorming, I found a "treasure"

Can the human heart regenerate?

"Although the regenerative ability is limited, it is possible to a certain extent." Over the past 20 years, Chen Jinghai, a researcher and doctoral supervisor at the Second Affiliated Hospital of Zhejiang University School of Medicine (hereinafter referred to as Zhejiang University Second Hospital), has been committed to research in the field of cardiac regeneration and repair.

In October this year, the 2024 Nobel Prize in Physiology or Medicine was announced. Two American scientists won this honor for their discovery of miRNA (microRNA) and its role in post-transcriptional gene regulation.

Chen Jinghai has been studying miRNA for many years: What role does it play in myocardial regeneration? How can we make myocardial cell regeneration stronger and last longer?

These questions are closely linked, and Chen Jinghai is getting closer to the truth by unraveling them again and again. "There will be many failures in the research process, but it is hard to resist the temptation to find the answer."

Full of enthusiasm, dedication, and perseverance... Chen Jinghai, who possesses these qualities, and the heart center team of Zhejiang University Second Hospital led by Wang Jianan, an academician of the Chinese Academy of Sciences, have taken a different path in the forefront of heart research.

He felt he had found a like-minded person.

Elegant and modest, speaking slowly and clearly, and making detailed notes after every interview question, Chen Jinghai always exudes the meticulousness and rigor of scientific research.

"In China, cardiovascular disease is the leading cause of death among the people, higher than cancer." Chen Jinghai entered the field of cardiovascular disease research after graduation. The accidental choice at the beginning gradually became his favorite career, and he immersed himself in it.

Before returning to China, Chen Jinghai worked in research centers such as the Sanford School of Medicine at South Dakota University, Harvard Medical School, and Boston Children's Hospital. In 2015, he was introduced to Zhejiang University Second Hospital.

Chen Jinghai chose Zhejiang University Second Hospital because he felt it was irreplaceable in terms of both its hard power and soft environment.

"I have been doing heart research. During animal experiments, I need a small animal ultrasound device to detect the heart's contraction and relaxation functions. This device is expensive. But at that time, Zhejiang University Second Hospital had such a device." Chen Jinghai said with a smile that for him, this was an extremely critical link. "If I didn't have this device, it would be difficult to carry out my research even if I came back. Moreover, Zhejiang University Second Hospital had already built the only key cardiovascular laboratory in the province at that time, which was very rare."

What Chen Jinghai likes most is the atmosphere of Zhejiang University Second Hospital. "I still remember the first time I went to Zhejiang University Second Hospital, I had a lively discussion with Secretary Wang Jianan and other experts in the cardiovascular field about professional issues. There was no nervous atmosphere of an interview at all. At that time, I had a feeling that I had found like-minded people."

In 2019, Chen Jinghai attended the BCVS Cardiovascular Foundation Annual Meeting in the United States. Photo provided by the hospital

How does the heart regenerate? Like mining, step by step

Can the heart regenerate? For ordinary people, this is a magical question, and it is also a research topic that Chen Jinghai has devoted a lot of effort to.

Chen Jinghai explained that cardiac regeneration refers to the ability of cardiac tissue to repair and rebuild itself after damage. Current research has found that lower vertebrates such as salamanders and zebrafish have the ability to regenerate their hearts; as for adult humans, the regenerative capacity of the heart is very limited, but there is still evidence that the heart may regenerate to a certain extent.

Why do we need to study cardiac regeneration? In China, nearly 50% of heart disease patients die from myocardial infarction and subsequent heart failure. The fibrotic scar formed by the loss of a large number of myocardial cells after myocardial infarction is the main cause of heart failure. Existing comprehensive measures such as drugs and interventions cannot completely repair the necrotic myocardium and improve the process of heart failure after myocardial infarction caused by fibrosis.

"If we can find the core link of cardiac repair and regeneration, then these problems can be solved fundamentally." Chen Jinghai's research work focuses on pathological reconstruction mechanisms such as myocardial cell regeneration and myocardial fibrosis after injury.

As early as during his postdoctoral period at Harvard Medical School, Chen Jinghai studied the role of miRNA in myocardial proliferation and regeneration. "We first discovered that the miR-17-92 gene cluster can promote the proliferation of myocardial cells in the embryonic period, perinatal period, and adulthood, and has a protective effect on cardiac function after myocardial infarction."

For Chen Jinghai and his team, this discovery is just the first step of the Great Wall, and they will continue to go deeper like mining.

There are 6 "members" in the miR-17-92 gene cluster. Which specific "member" is truly able to promote myocardial proliferation and regeneration?

"We found that miR-19 can promote the proliferation and regeneration of cardiomyocytes after myocardial infarction, reduce fibrosis, and protect heart function after myocardial infarction." In the process of studying miR-19, Chen Jinghai also found that the loss of the PTEN gene, the target of miR-19, can significantly increase the proliferation of adult cardiomyocytes after ischemic injury, reduce pathological hypertrophy and fibrosis of the myocardium after myocardial infarction, and protect heart function. At the same time, PTEN inhibitors have potential clinical translational value in cardiac regeneration and repair. In this research project, PTEN inhibition also affected the mitochondrial process. They focused on mitochondria and found that regulating them can promote the proliferation of cardiomyocytes and regeneration after injury.

These research results have been published in top international journals.

Looking back, Chen Jinghai and his team spent 10 years clarifying the role of the miR-17-92 and miR-19-PTEN axis in myocardial proliferation and regeneration. They linked each link closely to the next, leading to subsequent scientific problems step by step, and unraveling the mystery step by step.

Keep your curiosity and your mind will be open

Scientific research is a long process that involves failures, the impact of new ideas, and repeated subversions. Chen Jinghai expressed that all of these became interesting. "I like to read detective novels and the process of discovering the truth step by step. Scientific research is like solving a case."

Chen Jinghai made an interesting analogy: a rabbit jumps in front of you, and you shoot it. The rabbit is frightened by the gunshot and runs away. If you hit the rabbit's ear, and then shoot again, the rabbit can't hear the gunshot and doesn't run away, so you take the opportunity to shoot the rabbit to death. What conclusion would you draw based on the appearance? - The rabbit's ears may be responsible for jumping. "Of course, we all know that this is not the case. This is how scientific research works. There are many black boxes behind every phenomenon, and we need to dig and prove it step by step."

Chen Jinghai described this as a "mind-opening" process.

"I like the feeling of doing scientific research, raising questions, solving problems, and participating in the whole process of researching a problem. When the research results and data are obtained, I will be so excited that I can't sleep. That feeling of joy is incomparable."

Discovering and solving problems is not easy. Just like the study of heart regeneration, how can we grasp the "key point" among so many complex factors?

“You need to maintain your curiosity. You also need to be willing to accept challenges. For example, when your research does not match reality, do you dare to jump out in time? Can you accept new things in time?”

Before the idea of ​​cardiac regeneration was accepted, the widely accepted concept in the academic community was that myocardium is a terminally differentiated cell that cannot proliferate and regenerate. With the development of technology, researchers have gradually proved that regenerated myocardium is derived from the self-proliferation of existing myocardial cells, not from the differentiation and regeneration of stem cells. "When a new theory comes out, you must be brave and rigorous in verifying it and making breakthroughs in new directions."

The iteration and update of scientific research is very fast.

"Research needs to be updated in a timely manner. It does not necessarily mean starting over. We can make new developments while maintaining the original research foundation." Chen Jinghai said frankly, "Some of the research currently being done in my own laboratory is no longer exactly the same as before."

In the past decade, the emergence of massive biological information concepts, rapid development of artificial intelligence, and the emergence of more genetic lineages have all prompted researchers to constantly adjust and change.

In Chen Jinghai's opinion, this process is very exciting, but of course it is also accompanied by pain. "It can be said that it is painful and happy."

Chen Jinghai gave an example, the mice used in their research institute were initially hybrids of two or three genes, and it took about a year to obtain mice for experiments. Later, a new genetic lineage appeared, and four strains of mice were hybrids, and it took almost a year and a half to obtain mice for experiments.

"Our research models will also need to be updated accordingly. Although the process may seem more complicated, the accuracy of the experiment will actually be improved."

To do scientific research, you need a strong heart

Over the years, many people have asked Chen Jinghai: What should you do if you encounter bottlenecks in the scientific research process?

"I sometimes tell students that it might be better to focus on the problem itself rather than just looking at the results. Change your perspective and face it optimistically."

What Chen Jinghai said is actually what he has experienced: some research results were not achieved halfway through; some research results were just completed but others took the lead; some research results failed after investing a lot of time and energy... "Keep a strong heart, failure is common, but you have to believe that there will always be a moment of success."

Chen Jinghai and his team are committed to exploring the pathogenesis of heart disease and providing a theoretical basis and animal experimental verification for the prevention and treatment of cardiovascular disease from the perspective of molecular biology. "We are also actively promoting clinical transformation."

The scientific research process is long, but the hospital gave Chen Jinghai encouragement. "The hospital has supporting funds. The national key laboratories and provincial key laboratories have provided us with large-scale experimental instruments and equipment platforms, as well as platforms for cross-disciplinary talent exchanges. These have provided new ideas for our scientific research innovation and product transformation."

Of course, what Chen Jinghai is most grateful for is the rich academic atmosphere of Zhejiang University Second Hospital. "You can't do scientific research alone. Here, there are experts in different fields. When you encounter confusion, you can find people to ask for help. Their guidance can make you suddenly enlightened, and the efficiency is much higher than looking up books and information on your own."

For Chen Jinghai, there are still more "treasures" worth exploring in the field of cardiac regeneration. "I will write down all the problems I found during the scientific research process that cannot be studied temporarily in my memo. I already have several long pages. I think in the future, these will eventually have answers."