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Fused cells promising for tissue regeneration

Brenda Ogle and Nicholas Kouris.
Assistant Professor Brenda Ogle with PhD student Nicholas Kouris. Larger Image

Tapping a leukemia virus for both inspiration and function, Biomedical Engineering Assistant Professor Brenda Ogle and her collaborators are studying the biological effects of fusing adult stem cells with cardiac muscle cells, or cardiomyocytes. With funding from the National Institutes of Health, the researchers hope to learn more about cell fusion processes and, ultimately, to use that knowledge to develop therapies for heart attack patients.

During a heart attack, cardiomyocytes die. “Unfortunately, the body cannot produce new cardiomyocytes after such an event,” says Ogle.

Afterward, the body replaces those cardiac muscle cells with fibroblasts. Initially, fibroblasts help repair damaged heart tissue. Ultimately, however, fibroblasts form scar tissue instead of muscle tissue. That scar tissue has a very different mechanical composition from native heart tissue — and at best, says Ogle, the heart pumps inefficiently. At worst, it fails completely.

Fused with cardiomyocytes, stem cells could help restore lost heart muscle function.

Researchers generally acknowledge that cell fusion happens, yet they have just begun to study the mechanisms through which stem cells fuse with mature cells, and how, genetically, they form a single, functional cell.

It’s difficult to detect cell fusion — possibly because it occurs infrequently, but also in part because fused cells’ genetic material can mix, making the end product look like a single cell, says Ogle.

For their research, Ogle and her collaborators assumed cell fusion is rare. “We were wondering if there were ways that we could enhance cell fusion, knowing something about the ways that other entities fuse,” she says. “In this case, we were looking specifically at viruses.”

Viruses are “experts” at fusing with other cells. Ogle’s collaborators include virologists Yoshihiro Kawaoka, a professor of pathobiological sciences, and Stacey Schultz-Cherry, a visiting associate professor of medical microbiology, both of whom have extensively studied virus fusion proteins. Already, the researchers have shown that by adding a viral fusion protein to the stem cell, they can dramatically increase the incidence of fusion between stem cells and cardiomyocytes.

Now, looking at both cardiac and stem cell microenvironments, they are studying the fused cells’ phenotype, or observable characteristics. Drawing on Cardiology Professor Timothy Kamp’s expertise in cardiac electrophysiology, the group is examining the cells’ mechanical and electrical function, as well as their ability to proliferate.

The researchers also will induce an artificial infarction, or heart attack, in animals and inject stem cells expressing the fusion protein into the affected region to investigate how the cells engraft and to study their phenotype and function. The virus fusion protein is key, says Ogle, because a change in pH in its environment triggers the fusion process. “It isn’t until they’re injected into the myocardium and they see that change in pH that they open up and are ready to fuse,” she says. “And we think that’s one of the coolest aspects.”

Though Ogle and her colleagues hope cell fusion ultimately could help treat heart-attack patients, along the way, they are monitoring the fused cells for uncontrolled proliferation. “The more short-term piece is to really understand cell fusion — especially stem cell fusion,” she says. “If there is a way of controlling cell fusion, and if cell fusion is biologically relevant in a beneficial way, then it will have implications for tissue regeneration beyond myocardial infarction.”

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