Study led by experts at Cincinnati Children's sheds light at the cellular level on how heart valve tissues form. Findings eventually may improve survival odds for newborns with heart valve defects.
CINCINNATI, July 30, 2024 /PRNewswire/ -- Imagine a future where doctors could detect and treat potentially fatal heart valve defects months before a baby is born.
While this future is still a few years away, scientists have made significant progress by creating a detailed map of how human heart valves form. This new map, published July 24, 2024, in Nature Cardiovascular Research, will help guide future heart research.
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Healthy vs. defective heart valve formation: On the left side, representing healthy valve development, unidirectional blood flow induces Jag1 production in valve endothelial cells (VECs), which activates NOTCH2-mediated Notch signaling when these cells contact Elastin-expressing valve interstitial cells (VICs). This process promotes downstream elastogenesis-related gene expressions. On the right side, representing defective development, a lack of APOE in pulmonary stenosis patients suppresses Notch signaling, leading to elastogenesis defects.
Emerging blueprint for replacement valves that can grow
Heart valves might be small, but they're incredibly important. Doctors have been replacing damaged heart valves in adults for many years, and sometimes they can save newborns with artificial valve transplants.
But these artificial valves aren't perfect. They don't have living cells, so they can't form a completely normal valve. They also don't grow with the child, which means the child might need several risky surgeries as they get older.
"Engineered human heart valves with the appropriate cell types for transplantation would avoid repeated surgeries in babies and address the donor valve shortage," says corresponding author Mingxia Gu, MD, PhD, an expert in molecular and cardiovascular biology at Cincinnati Children's. "Now, we've achieved an unprecedented understanding of the cellular composition of human heart valves and how fetal heart valve tissue changes over time. This is a crucial first step for future human valve engineering."
How do heart valve leaflets form?
The human heart has four valves that control the flow of blood through the heart's chambers. Each valve has two or three thin and fragile-seeming leaflets that open and close more than 2.5 billion times across a lifetime.
When a baby is growing in the womb, the cells that make up these leaflets change completely. At 14 weeks, the leaflets are mostly made of complex sugars. By 36 weeks, they turn into three-layered tissues with a mix of flexible and stiff fibers.
If these leaflets don't form correctly, it can cause serious heart problems.
Heart valve birth defects are rare. The most common type, called bicuspid aortic valve, occurs among an estimated 0.5% to 2% of people. This condition occurs when two of the normal three leaflets of the aortic valve stick together. Those affected need life-long monitoring may require valve replacement surgery at some point.
Other conditions that can involve defective heart valves include valve prolapse in Marfan syndrome, a narrow pulmonary valve in tetralogy of Fallot, and a missing aortic valve in hypoplastic left heart syndrome.
Unexpected role played by the gene APOE
The Cincinnati Children's research team studied healthy and faulty heart valves all the way down to the single-cell level. They documented in unprecedented detail how various cell types signal each other to form valve tissues.
In a key finding, the team discovered a cell type that expresses high levels of the gene APOE. This gene needs to work in concert with another gene called NOTCH2 to make the elastin fibers essential for heart valve function. The involvement of APOE was surprising because previously the gene had been known only for its role in atherosclerosis and Alzheimer's disease.
The paper further describes signaling "crosstalk" among key genes as they instruct developing cells to form the heart valve tissues. This process continues as the fetus grows and continues after birth until the heart reaches its full adult size.
"The finding of APOE as the top regulator in modulating elastin formation during early valve formation could yield a new angle for clinicians to understand heart valve underdevelopment," says co-corresponding author Yifei Miao, MBBS, PhD.
How can these findings help people with heart valve defects?
Researchers will need several more years to figure out how to use these new discoveries to help people. Knowing which genes are key for making the various parts of heart valves—and which ones function incorrectly in babies with heart valve defects—will provide vital clues for creating future gene or cell therapies.
One exciting idea is to use the new atlas to engineer a "human valve" for valve replacement therapy. Currently, replacement valves include mechanical devices, biological ones made from cow or pig tissue, and some human valves obtained from donated organs. The new atlas may help scientists build or "grow" human-tissue valves in the lab.
"This atlas provides insights into the similarities and differences among the four human valves, enabling more precise valve engineering and deep understanding of the valve-specific phenotypes in patients," Gu says. "The newly discovered APOE+ valve cell type could be crucial for seeding onto an engineered valve scaffold to mediate elastin fiber formation, which is essential for valve remodeling and function."
About the study
Cincinnati Children's co-authors also included Ziyi Liu, MD, Yu Liu, PhD, Zhiyun Yu, PhD, Cheng Tan, MD, Nicole Pek, BSc, Anna O'Donnell, BS, MBA, Minzhe Guo, PhD, Katherine Yutzey, PhD, and David Winlaw, MBBS, MD, (now at Lurie Children's Hospital).
Co-authors also included experts with the Stanford School of Medicine, the University of Michigan, the University of Washington, and the Icahn School of Medicine at Mount Sinai, New York.
Funding sources for this study include support from Additional Ventures (1019125), an Endowed Scholar Award from Cincinnati Children's, two grants from the Chan Zuckerberg Initiative (CZF2019-002440 and CZF2021-237566), and two American Heart Association Predoctoral Fellowship grants (1013861 and 906513).
This research was further supported by the Cincinnati Children's Heart Institute Biorepository, the Discover Together Biobank, the Division of Pulmonary Biology, and core research facilities in Pathology and Confocal Imaging.
SOURCE Cincinnati Children's Hospital Medical Center
