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.
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.
View original content to download
multimedia:https://www.prnewswire.com/news-releases/new-atlas-of-human-heart-valve-development-may-guide-next-gen-therapies-302210306.html
SOURCE Cincinnati Children's Hospital Medical Center