Discovery; Heart

Helping the heart heal itself: The science of regeneration

Discovery; Heart

Dr. Hesham Sadek's lab at UT Southwestern has advanced the science of regenerating heart cells in hopes of someday helping victims of heart attack or heart failure recover their function.

Most muscles in the body have an innate ability to heal themselves. Following an injury, cells divide and fuse with existing muscle fibers to regenerate and repair the damage.

Before birth, the human heart is an inferno of rapid cellular division. But once we’re born, the rush of oxygen from our first few breaths provokes cells that cause the heart to beat – called cardiomyocytes – to grow rapidly instead of divide.

And the heart’s power to regenerate is lost.

Over the last decade, our team of doctors and scientists at UT Southwestern have focused on isolating when and why the heart stops regenerating. We’ve discovered two proteins – Meis1 and Hoxb13 – that partner to halt heart cell division. When these two genes are deleted or inhibited in the lab setting, heart cells revert to earlier developmental function, decreasing in size and multiplying more vigorously.

In other words, we have shown it’s possible to return moderately damaged heart cells to near-normal function. By harnessing this science, we hope to develop medications that can heal damaged heart tissue following a heart attack, heart failure, or cardiac injury.

Whereas it could still take years for clinical applications to reach patients, we are now significantly closer to regenerating heart muscle and saving lives.

Related reading: NIH $7.5 million award will support Dr. Sadek's ongoing research into heart regeneration

How does oxygen halt heart regeneration?

To fully understand why human heart muscle doesn’t regenerate on its own, we had to look back to its development in utero, where maternal circulation does all the hard work of providing oxygen-rich blood to the fetus.

In the womb, the fetal oxygen saturation is only 50-60% (compared to 100% after birth and throughout life). Shunts, or small passageways, in the fetal circulatory system mix the maternal and fetal blood, providing enough oxygen for fetal cells to develop.

These shunts are switched off after birth, when the newborn’s first breath causes the shunts to close and the heart begins to pump blood with a much higher oxygen saturation. Coincidentally, the pressure inside the heart increases. These two factors create a perfect storm, and the heart becomes the most energy-demanding organ in the human body.

As a result, the heart quickly builds up its energy-generating machinery, tiny cellular factories called mitochondria. Mitochondria use oxygen to provide liquid energy (ATP). Unfortunately, they also create a toxic environment filled with damaging chemicals called reactive oxygen species.

We believe this series of events damages the cardiomyocytes in the heart that are programmed to keep dividing. There are some specific benefits to this process: It reduces the risk of spreading potentially harmful mutated cells, which can cluster as tumors, damage the organ, and spread throughout the body. Halting this process, though, is likely what stops the heart’s inherent ability to regenerate. But there may be a solution. What if we can prevent or reverse this pathway to oxygen damage?

To make that idea a reality, we have embarked on a research project with the German Aerospace Center in Cologne, Germany.

Can hypoxia reactivate heart regeneration in adults?

the regenerative effects of hypoxia therapy on damaged hearts
Researchers at UT Southwestern are investigating the regenerative effects of hypoxia therapy, or prolonged periods of low oxygen, on damaged heart tissue.

At the top of Mount Everest, the oxygen level is 7% – approximately 1/3 of the oxygenation at sea level. Nothing can survive for long at the summit, particularly humans.

However, 7% oxygenation might be a sweet spot for heart cell regeneration. Our researchers placed injured cardiomyocytes in a dish in our hypoxic lab at that concentration. After two weeks, the damaged cells started to divide and regenerate.

Researchers at the German Aerospace Center, home to the world’s largest oxygen chamber, are taking these findings to the next level through the MyoCardioGen study. Working with mountaineers and extreme athletes who are acclimated to low oxygenation, they hope to establish a starting point for clinical trials.

Benjamin Levine, M.D., Professor of Internal Medicine/Cardiology at UT Southwestern and founder and Director of the Institute for Exercise and Environmental Medicine (IEEM) at Texas Health Presbyterian Hospital Dallas, introduced us to our Cologne colleagues. We serve as cardiologic consultants for MyoCardioGen – reviewing their imaging and offering ideas to adjust their protocols, which are derived from our foundational research.

Together, we hope to determine whether patients with heart damage from disease or injury could regain partial or full heart function through hypoxia therapy, without damaging other vital organs such as the kidneys or brain.

What is the future of heart regeneration research?

Even if human heart hypoxia trials prove to be overwhelmingly successful, it would be challenging for all heart patients to receive this experimental hypoxia treatment. The cost of building such facilities is unsustainable, and hypoxia is physically taxing for healthy patients, let alone those who rely on mechanical heart pumps or other life-preserving devices.

But where there is a will, there is a way. Specifically, we recently identified two transcription factors called Meis1 and Hoxb13 that coordinate the loss of the ability of the heart to regenerate. But can we engineer drugs that reverse this process by targeting these transcription factors?

Over the last five years, a team of medicinal chemists and structural biologists at UT Southwestern has been working to identify medical targets in the genetic pathways that stop heart cell division.

In 2021, UT Southwestern submitted a patent for a drug formulation that our preliminary research suggests can target transcription factors that shut off the heart’s ability to regenerate such pathways.

At least four pharmaceutical companies are working toward heart regeneration implants, injections, and tissue patches. Researchers are beginning to develop viral vector therapies, in which a specialized virus delivers a healthy gene directly to certain heart cells to activate or inhibit a specific genetic action.

What’s more, we are working on research at UT Southwestern to grow a human heart from induced pluripotent stem cells, which are stem cells that are reprogrammed from adult cells. These cells are programmed with transcription factors from blood samples that steer them to become heart cells. Grouped together – in the right place, position, and direction – these heart cells become an organoid, which we have shown can beat spontaneously inside a petri dish.

Along with reactivating heart regenerative properties, we are studying whether temporarily reducing the heart’s workload can restore the heart cells’ ability to divide and heal from mild to moderate heart failure damage.

Intriguing research suggests that some patients could have their mechanical heart pumps weaned and ultimately removed – without having a transplant – and resume fairly normal heart function due to spontaneous tissue recovery. Upon further research, we could eventually develop guidelines for who could potentially avoid needing a transplant and when to remove a pump.

However, we predict that this type of therapy would have to be exquisitely timed. Once the heart becomes too damaged, restoring adequate functionality is not likely.

'We will be able to regenerate the human heart'

The lab of Dr. Hesham Sadek, a cardiologist and researcher at UT Southwestern, has made multiple discoveries that move science and medicine much closer to being able to regrow damaged heart muscle.

A few closing thoughts

“Growing a new heart,” or heart regeneration, might sound like the fantastical invention of a science fiction novelist. But the research and the results are real.

More importantly, this work, which continues to expand around the world, could ultimately improve the quality of life for millions of patients with mild to moderate heart disease. It can also slow or prevent their progression into severe heart disease and reduce the number of people who need a heart transplant.

In true mountaineering spirit, the race to the summit will be laced with unpredictable challenges. However, in the end, the victor will be the patients and their families who struggle with heart disease.

To visit with a cardiologist about heart disease treatment options, call 214-645-8000 or request an appointment online.