A study published in the journal Biomaterials finds that the rhythmic pulsation of cardiac muscle cells is a driving force in the initial formation of heart valves.
The heart forms as a simple U-shaped tube of tissue, comprised of three layers.
A layer of cardiac muscle cells begin to pulse even before blood vessels are formed. Beneath the muscle is a layer of "cardiac jelly," and below that is a layer of endothelial cells that will transform into valvular interstitial cells (VICs).
Where the heart valves form, endothelial cells embed themselves into cushions of cardiac jelly.
The endothelial cells transform into VICs, and these cells co-ordinate the transformation of the cardiac jelly into the two or three flaps (called "leaflets") that comprise the valve and control the flow of blood to the heart by opening and closing.
Heart valves are susceptible to damage from disease, cancer, aging, heart attacks and birth defects. Around 40,000 babies are born with congenital heart defects in the US each year, so creating a working heart valve that could be used in patient transplants has been a priority for some time.
Artificial valves currently exist, but they are made out of plastic, so children born with congenital heart defects must endure multiple surgeries to have these replaced as they grow up.
Growing artificial heart valves out of human cells
The solution that the researchers behind the new study are working toward is to create an artificial valve out of human cells that will grow with the child.
"For the last 15 years, people have been trying to create a heart valve out of artificial tissue using brute-force engineering methods without any success," says W. David Merryman, assistant professor of Biomedical Engineering at Vanderbilt University in Nashville, TN.
"We decided to take a step back and study how heart valves develop naturally so we can figure out how to duplicate the process."
To do this, Prof. Merryman led a team of engineers, scientists and clinicians in a series of experiments on chicken hearts. Most animal heart valves go through their cycle about 1 billion times in their lifetime, but chicken and human heart valves - which develop in similar ways - cycle 2 to 3 billion times.
In spring 2012, the Vanderbilt team announced that they had identified previously unknown genes and molecular pathways associated with the formation of health valves. Their latest work - examining the "mechanical forces" influencing heart valve formation - completes the gaps in the team's knowledge.
"The genetic study gave us the list of the basic parts - the hardware - required to build a heart valve and this latest study provides us with the information we need about the environment that is required," says Prof. Joey Barnett, co-principal investigator on the project.
"With this information, we should have what we need to create valvular interstitial cells, which are the basic building blocks of heart valves."
Rhythmically beating cells help heart valves to form
A standard procedure for observing the early stages of heart development is to extract the heart of a chick - at the point when it is the size and shape of a comma on a printed page - and place it in a cell culture dish with collagen gel.
But this alone was not suitable for studying the mechanical forces involved in the formation of the valves.
The researchers wanted to measure the pulsation of the heart cells to see how this influenced valve formation, so they created a computer program that analyzed sequences of microscopic images on the surface of the gel.
"We have discovered that mechanical forces are important when making baby hearts," says Mary Kathryn Sewell-Loftin, the Vanderbilt graduate student who created the computer program.
Studying the locations on the computer map where VICs were formed, the team determined that the VICs form preferentially in areas of "high strain" caused by the rhythmic expansion and contraction of cardiac muscle cells.
"The discovery that the deformations produced by the beating cardiac muscle cells are important provides an entirely new perspective on the process," says Prof. Merryman.
Next, the Vanderbilt team will work with a stem cell researcher to produce their own endothelial cells, from which they hope they can produce human VICs. Once they have the VICs, the researchers believe they should be able to grow artificial human heart valves in a bioreactor.