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Issue 22013

The Heart of the Matter

Eden McCleskey

Photos by Allen Kramer

What would it mean to thousands of children if scientists could grow a human heart in a laboratory?

Unlocking the answer to that question — creating that reality — drives the research and work of scientists and surgeons alike who are developing novel treatment options for children with heart defects.

With a new and promising method under investigation, researchers are experimenting with growing healthy replacement heart tissues in the lab and implanting them in the patient’s heart. Texas Children’s is a major site for this collaborative, multi-institutional research that’s helping develop powerful new ways to heal hearts.

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The Search for the Perfect Cell

Jeffrey Jacot, Ph.D., is the head of Texas Children’s Pediatric Cardiac Bioengineering Laboratory. Jacot is an unassuming scientist. Rather than diplomas and journal covers, his office is filled with pictures of his 7-year-old son, and he is perpetually self-effacing when talking about his work. But with a CV that includes an undergraduate degree in chemical engineering from University of Colorado, a Ph.D. in biomedical engineering from Boston University, and a distinguished academic career with several major breakthroughs before he’s even come up for tenure, Jacot brings considerable expertise and vision to the challenges at hand.

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Those challenges are significant — especially when his work revolves around getting enough of the “right” cells.

All laboratory-grown tissue begins with a source of human cells — typically stem cells, the precursor cells that form all of the tissues of the body.

“A major focus of our lab is figuring out what stem cell sources are easiest to turn into heart tissue and how easy it is for us to access enough of them,” Jacot said.

Embryonic stem cells are the gold standard for stem cells, but they are difficult to come by, and as they aren’t the patient’s own cells, they are genetically different from the patient. This genetic difference may provoke a destructive response from the patient’s immune system.

“There’s some controversy over whether embryonic stem cells are immune-protected or immune ‘neutral,’” Jacot said. “Some studies have shown that they don’t produce an immune response. But the surgeons I’ve talked to have said they would feel better using tissue that came directly from a patient’s own genetic material.”

A 2008 discovery holds some promise. A researcher in Japan found a way to turn other types of cells into ones that look and act almost exactly like embryonic stem cells. These cells, called induced pluripotent stem cells, act as sort of a blank slate, allowing a scientist to, for instance, take a skin cell from an adult, turn it into a “blank slate” and then turn that into something else. But some blank slates are easier to turn into cardiac cells than others.

“Because Texas Children’s now has the Pavilion for Women and is doing a lot of cutting-edge work in the Fetal Center, we have a fairly high level of access to amniotic fluid stem cells,” Jacot said. “Fetuses slough off cells into the amniotic fluid as they develop, and by taking a small amount of the mother’s amniotic fluid, we can turn them into induced pluripotent stem cells and see what kind of cardiac cells we can turn them into. We’ve found that they make vascular cells really well, but they’re not as good at making heart tissue yet.”

Joining Forces

This intramural collaboration between Jacot’s lab and Texas Children’s Pavilion for Women echoes a larger research collaboration between Texas Children’s, Rice University and several other local institutions. It’s a relationship that resulted from a fortuitous meeting between the head of pediatric heart surgery at Texas Children’s Hospital and a young researcher at Rice University.

Charles D. Fraser, M.D., surgeon-in-chief at Texas Children’s Hospital, is a leader in the fields of pediatric, neonatal and in-utero heart surgery and a pioneer in the use of ventricular assist devices (VADs) such as the Berlin Heart.

Like other heart surgeons, Fraser had read with interest about efforts in laboratories across the country to turn stem cells into heart muscle tissue or heart valve tissue. But he had been frustrated with what he saw as a lack of alignment between clinical practice and basic science research.

Even though he was leading the largest clinical center for congenital heart repair in the country, he had virtually no link to any of the basic science labs that were attempting to recreate human heart tissue.

When Fraser met Jane Grande-Allen, Ph.D., things began to change. It was the beginning of a new chapter in research at Texas Children’s. Grande-Allen is a researcher at Rice University whose concentration is bioengineering approaches to heart valve repair — literally seeking ways to grow new heart valves in the laboratory.

“When we started talking,” Fraser said, “I mentioned how many operations we did per year and how much human valvular tissue we had access to, and her jaw dropped to the floor. And she mentioned some of the things that they were working on in the lab, and my jaw dropped.

“Obviously, it would be very helpful to her team to have access to our samples and to be present at some of our surgeries to understand what the real issues are,” Fraser said. “And it would be equally beneficial for us clinicians to understand what is going on and what is possible on the research side. It was very clear that we were not working as closely together as logic would suggest was profitable.”

Fraser and Grande-Allen began a collaboration that included shared grant funding and the involvement of a number of graduate students. Ultimately, it also led to the founding of the Pediatric Cardiac Bioengineering Laboratory and the recruiting effort that would bring Jacot to Texas Children’s.

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From Cells to Tissue Specificity

The work in Jacot’s lab is pushing beyond the identification and isolation of stem cells into investigation of ways to get those cells to grow into specific shapes. The team is currently researching biomaterials that they can use to shape and control the way the tissue grows.

“We need to use other types of materials as a kind of mold or scaffold that the cells will grow on but will eventually go away and degrade, being replaced by materials that the cells make themselves,” Jacot said. “It’s kind of like Goldilocks. You need material that’s not too stiff, not too soft, that allows the cells to contract but also gives a little bit of resistance.

“We’re working with a lab at Rice on using liquid crystal elastomers — like you might find in your LCD clock display — which align in a certain way when you put a current across them. We recently published on a gelatin-chitosan blend. Chitosan is what the shells of shrimp and crawfish are made of, and it worked really well.”

The lab’s most promising effort so far is a patch of living heart tissue that could be used in heart repair surgeries. The patches currently used to repair congenital heart defects are made of synthetic fabrics or are taken from cows or from the patient’s own body.

“These types of procedures have good short-term outcomes, but long term, there’s an increase in complications,” Jacot said.

In the approach Jacot and team are investigating, a scaffold is designed to support the growth of healthy new tissue and is studded with living heart cells. These cells are allowed to reproduce in the lab, and then the scaffold and the new heart tissue can be implanted in the damaged heart. Over time, the scaffold is designed to degrade, leaving behind a heart repaired with real human heart tissue.

Seokwon Pok, Ph.D., a post-doctoral student who works in Jacot’s lab, came up with the idea for the heart patch and was lead author in a study that was published in the journal Acta Biomaterialia.

The research of Drs. Jeffrey Jacot and Seokwon Pok revolves around production of a bioscaffold material seeded with living heart cells designed ultimately to promote the growth of healthy new heart tissue.

The research of Drs. Jeffrey Jacot and Seokwon Pok revolves around production of a bioscaffold material seeded with living heart cells designed ultimately to promote the growth of healthy new heart tissue.

“We think that using living tissue will dramatically improve long-term outcomes,” Jacot said. “You won’t have a scar response, you’ll have something that is actively conducting and contracting, rather than disrupting the electrical signal and contraction of the heart.”

Beyond that, with living tissue, Jacot believes surgeons would be able to do many kinds of reconstructions and repairs that simply aren’t possible right now.

“In order to repair a major area of a ventricle, you can’t just put a sheet of plastic in,” Jacot explains. “You need something that can contract and be functional right from the start.”

For Fraser and Grande-Allen, the recent publication of Jacot’s and Pok’s research is a sign that they are moving in the right direction.

“We think this will help us build a platform on which major advances can occur in replacement of structurally deficient elements of the heart,” Fraser said. “Figuring out how to build these heart patches, and how they can electrically communicate, gives us much more insight into other opportunities for development, up to and including the ‘holy grail’ of growing an entire heart in the lab.”

So what exactly would it mean to be able to grow a human heart in a laboratory?

“For one thing, it would eliminate the need for organ donors,” Jacot said. “The number of transplants has plateaued, and even if we found a way to drastically improve the number of people who donate, it will never even come close to meeting the demand. Also, by using a patient’s own stem cells to create the lab-grown heart, we could eliminate failures based on rejection and immune-protection that go along with using organs from another person’s body.”

Critical Mass

Recently, Fraser, Grande-Allen, Jacot and several other researchers in the Houston area have come together to form a collaborative called the Texas Center for Regenerative Medicine.

“We’re putting together a real critical mass of people with a lot of knowledge about the huge range of tissues that actually go into a heart, as well as other organs in the body,” Grande-Allen said. “Our group includes teams of researchers from Texas Children’s Hospital, Texas Heart Institute, Rice University, Baylor College of Medicine, The University of Texas Health Science Center, UTMB and Texas A&M, and our goal is to get together regularly to find out what everyone is doing and to apply for large collaborative research grants to help us advance our field of study.”

Scientists associated with the collaborative are looking at everything from stripping a human cadaver heart down to the cartilage and then rebuilding it cell by cell using tissue grown in a lab; to creating heart patches; to injecting viruses into hearts to help them perform better.

“Somewhere along the road here, we are going to figure out that one approach works better and has more promise, and we’re all going to shift accordingly,” Jacot said. “That’s what’s so exciting about this type of research. You never really know where you’re going until you get there, and even then, you’ve never fully arrived at a destination — you’ve just veered down a new path.”

Creating a Better Solution for Pediatric Heart Valve Replacement

Eden McCleskey

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Drs. Henri Justino, Daniel Harrington and Kwonsoo Chun examine the prototype valve in a high-cycle tester.

Henri Justino, M.D., C.M., director of the C.E. Mullins Cardiac Catheterization Laboratory, is something of a magician when it comes to repairing a child’s heart in the least invasive way possible. He and his colleagues in the cath lab can remove a blockage, close a hole in the heart, and replace a defective heart valve using thin, flexible catheters and some deft flicks of the wrist, leaving no trace of their efforts other than a tiny incision near the patient’s hip.

One thing that has consistently bothered him, however, is the lack of available options for children with defective heart valves.

“Compared to the adult market, the pediatric market is simply too small for companies to invest in,” Justino said. “Seventy-five percent of children who need a valve replacement need a pulmonary valve, but there’s only one kind available today that can be delivered by a catheter approach and is approved for use in the pulmonary position. It’s expensive and hard to come by. We need another option.”

Justino and his partners — Daniel Harrington, Ph.D., at Rice University, and Kwonsoo Chun, Ph.D., at Baylor College of Medicine — are on a mission to create an artificial pediatric pulmonary valve that can be delivered by a catheter-based approach into the heart.

“Right now, we are working on getting the mechanics right,” Justino said. “We need a solid valve that works well, opens and closes well with every heartbeat, and is designed to last.”

Getting the valve’s mechanics right is no small feat. It must be small, thin and flexible enough to snake through a young child’s veins and through the chambers of the heart. Once it’s in the right place, it needs to expand to full size, anchor in place with no sutures or adhesive, and be durable enough to last many millions of cycles in a child’s heart, which beats up to twice as fast as an adult’s. They’re also trying to design the valve so that it can grow with a child over time.

“We’ve definitely got some challenges,” said Justino, who compares catheterization to a mechanic trying to fix the motor on a car while it’s still running. “We’re doing all sorts of procedures on the heart without ever having to stop the heart or put the patient on a heart-lung machine.”

And that’s the point — to fix the heart with as little disruption as possible.

“Open heart surgery does work very well, and it is a very good option if it’s your only option,” Justino said. “If you can get the very same result without having the chest opened, without a long scar, without using an artificial machine to circulate blood through your brain, and if you can go home the very same day instead of staying in the hospital for several days — even go to school the next day — why would you not want that?”

After three years of development, Justino, Harrington and Chun have a working prototype and are very close to completing their first milestone, which is to prove that it works in the lab setting and meets the criteria the FDA requires of valves. The next phase is animal testing: How does this device perform when it’s placed in a living organism, in contact with organs, tissue and blood? The final step, human testing, may be several years away depending on funding and how well the first two stages go.

“Our long-range goal, after all of this is complete, is to see if we can coat the valve with living tissues and various kinds of cells to make the device more biocompatible with the patient, similar to what Dr. Jacot and his team are doing,” Justino said. “But that’s a long way away. For now, our main goal is to get the best performance we can from this valve and then get it on the market — helping children — as quickly as possible.”