The lub-dub of a healthy heart  pg. 4

Let’s back up.

When the heart initially develops during the third week of human embryogenesis, it is a simple tube with two epithelial layers of cells: an inner endocardium, which will form the inner lining of the heart, and an outer epimyocardium, which will become the heart muscles that will pump for the lifetime of the individual.

In between the two layers is extracellular matrix, gelatinous material void of cells called “cardiac jelly.” At the sites where the heart valves will take shape, Barnett explains, the tube constricts and the cardiac jelly expands, becoming a bulge called the cushion.

“If you look at a heart at this stage of development the bulge is already functioning as a valve,” Barnett says. “It’s very resilient, so when the heart pumps, the blood moves through and then this bulge snaps back into place to prevent blood from flowing backwards.”

Next, a signal (or signals), most likely made by muscle cells, causes some of the endocardial cells to change from epithelial-type cells to connective tissue mesenchymal-type cells, migrate into the cardiac jelly and populate it. This change in cell type, known as “epithelial-mesenchymal transformation” (EMT), is a crucial step in the formation of each of the tissues – heart valves, teeth and pancreas – that the SysCODE consortium will attempt to build in the lab.

Barnett’s group and others have extensively studied the EMT process in valve-forming cells in embryonic chick hearts.

His team removes the cushion region from a 2-day-old developing chick embryo, grows it in culture, and adds or subtracts growth factors to evaluate which factors affect cell invasion and proliferation. The group also injects viruses into chick embryo hearts, which are the size of a comma on this page, in order to change gene expression and assess the impact on transformation.

“We know a lot about the transformation process,” Barnett says, “but then next we talk about magic happening. You’ve got the cushion full of cells, and by some combination of genetic and hemodynamic forces, that cushion gets remodeled into what we call a heart valve.

“That’s where we’re heading with SysCODE, is to understand – and eventually replicate in vitro – that remodeling process.”

Heart in a Petri dish

Barnett, who earned his Ph.D. in Pharmacology from Vanderbilt in 1986, remembers exactly when he fell in love with the idea of studying the heart. He was visiting Harvard cardiovascular researcher Jonas Galper, M.D., Ph.D., to talk about a postdoctoral fellowship when Galper suggested they take a look at the embryonic chick heart cells the group was just beginning to grow in culture.

“When I saw those beating heart cells, I knew immediately that I would be working with Jonas,” Barnett recalls. “Here was a cell that was beating in culture, that had a biological response that you could measure – a cell that you could use to really ask questions about how signaling molecules affect and regulate the biology.”

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