Regenerative medicine is the physiological equivalent of turning back the clock — by replacing diseased or damaged organs and tissues with healthy, proliferating cells that can restore normal function.
For the first time, we are able to deploy cells as medications. Cells can replace and repair and restore function in the body in a way that drugs and biologicals cannot.
–Jakub Tolar, M.D., Ph.D., dean of the Medical School and director of the University's Stem Cell Institute
At the core of many approaches to regenerative medicine are stem cells, which have the ability, depending on environment and chemical stimuli, to turn into any kind of specialized cell. Some researchers are working to direct stem cells to take root at the site of an injury and repair or replace damaged tissue. Others are trying to induce specialized cells, such as heart muscle cells, to behave more like stem cells, by dividing and proliferating to replace dead tissue.
Regenerative medicine received a jump-start in Minnesota in 2014 when the Legislature created Regenerative Medicine Minnesota, providing about $4.5 million a year for 10 years for stem cell research and education throughout the state.
Here are a few ways state, federal, and private support has boosted the work of University of Minnesota scientists who aim to enhance stem cells’ ability to heal the body, including our mightiest muscle — the heart.
The heart patch for mice is about the size of a sequin. Now the team is working on a larger patch for pig hearts, which are more similar to human hearts. (Image courtesy of Brenda Ogle, Ph.D.)
Patching a broken heart
When scientists discovered they could turn pluripotent (reprogrammable) stem cells into cardiac muscle cells in the laboratory with nearly 100 percent success, they started searching for ways to use these muscle “progenitor” cells to repair heart damage from an injury such as a myocardial infarction.
Initially, they tried growing suitable progenitor cells in the lab and injecting them into the heart near the site of the dead muscle tissue, but they soon discovered that few of these cells took hold to produce living, beating tissue.
Brenda Ogle, Ph.D., an associate professor in the University’s Department of Biomedical Engineering, tried something different. She printed a mesh 3-D heart “patch” of natural collagen and other protein and seeded it with heart cells derived from human stem cells, a technology she describes in a paper published early this year in Circulation Research.
“The impetus comes from our desire to organize the cells before putting them into the heart — that was the idea,” says Ogle, who is a member of the University’s Stem Cell Institute and Lillehei Heart Institute. “If we can organize them and they can propagate a signal from one side of the patch to the other, they should be able to bypass the scar or the injured area.”
But not just any mesh will do. Conventional 3-D bioprinting produces a mesh that’s too coarse; the stem cells don’t settle in and interact with the matrix around them.
Working with colleagues at the University of Wisconsin, Ogle used a printing technique known as multiphoton fabrication to lay down a protein mesh with gaps as small as a single micron (one-millionth of a meter), about 100 times finer than most 3-D bioprinters can produce. “That was the critical part,” says Ogle.
The team implanted the mesh with about 50,000 heart muscle cells, smooth muscle cells, and endothelial cells (which line blood vessels) derived from human pluripotent stem cells. The cells settled into the mesh, spontaneously aligned with one another, and began to contract and relax like normal heart muscle cells — “a very promising outcome,” says Ogle. “When we found that, we knew that here was something we should try to transplant in an attempt to improve function of a failing heart.”
Ogle’s group transplanted patches into mice, placing the sequin-sized mesh over a portion of the heart damaged by a myocardial infarction. After four weeks, more than 11 percent of the transplanted cells had survived and merged with the mice’s heart tissues. Though the hearts did not beat as strongly as normal mouse hearts, the team found a significant increase in function, Ogle says.
Now Ogle is working on a National Institutes of Health grant to perform similar transplants in pigs. She envisions a day, perhaps within just a few years, when the mesh patch is seeded with human pluripotent cells from a stem cell “bank” and implanted in a patient within hours of a heart attack — truly mending a broken heart.
Jop van Berlo, M.D., Ph.D., is looking for ways to stimulate new heart muscle cell development to repair an injury or defect. (Photo: Jim Bovin)
Unlocking heart muscle repair
If only humans were more like zebrafish. Then our heart muscle cells could simply generate new cells to repair heart damage.
“It would be really handy, but for unknown reasons it doesn’t happen in our bodies,” says the Medical School’s Jop van Berlo, M.D., Ph.D., who holds the Lois and Richard King Assistant Professorship in Medicine and is a member of the Lillehei Heart Institute and Stem Cell Institute. “As a consequence, we can’t really regenerate from an injury, like myocardial infarction.”
Van Berlo is trying to unlock the genetic pathways that might allow humans to respond more like zebrafish — creating more heart muscle cells to restore a strong, reliable heartbeat. “If we could entice these cells to generate more cardiomyocytes [heart muscle cells] in a relatively short time span, we might be able to regenerate our hearts better after such an injury,” he says.
Among van Berlo’s collaborators is Yasuhiko Kawakami, Ph.D., associate professor in the Department of Genetics, Cell Biology, and Development, who studies the ability of zebrafish to regenerate heart cells. “It’s interesting for me to work with him so that we can see why zebrafish have this ability and mice and humans don’t,” says van Berlo.
Van Berlo recently received a $300,000 award from The Hartwell Foundation to fund exploration of a new treatment for hypoplastic left heart syndrome (HLHS). Children with the congenital defect have underdeveloped hearts with too few muscle cells to pump blood effectively throughout the body — and their bodies are unable to generate more heart muscle cells to take up the slack.
The Hartwell funds will help him test a new approach to adding muscle cells to the heart by unlocking its ability to form new cells — ultimately improving its function. Using computerized high-throughput analysis, van Berlo has identified a number of genes that appear to play a role in regulating heart muscle cell division. He found that switching off these genes stimulated heart muscle cells in culture to begin to divide and multiply. Now he wants to identify which of these genes might be tweaked — either in culture or in the body — to stimulate new heart muscle cell development and help repair the HLHS defect.
There are two ways the body might recruit more heart muscle cells: by signaling resident stem cells to turn into new heart muscle cells, or by stimulating existing muscle cells to divide and multiply. “I’m looking at both of these approaches,” says van Berlo.
“My ultimate goal would be to have this happen inside the body so that you wouldn’t have to take cells out,” he says. “You would essentially just take a pill that would stimulate the progenitor cells to become contractile cells.”
Finding such a drug would unlock the potential to treat many types of heart conditions, from congenital defects to the ravages of a heart attack, by helping the body heal one of its most vital organs.
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