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Great expectations

Doris Taylor, Ph.D., and her team have found that bone marrow stem cells can reverse blood vessel damage in animal models of atherosclerosis.

The potential to transform medicine looms large as the Stem Cell Institute embarks on its second decade of discovery

Amid the fanfare over the University of Minnesota’s new TCF Bank Stadium, scientists working in labs across the street from it are engaged in quieter but higher-stakes activities. These leading researchers at the University’s Stem Cell Institute along with others performing stem cell research across the campus may hold in their Petri dishes the keys to unlocking the mysteries of diabetes, cancer, heart failure, brain injury — even aging.

Established in 1999, the Stem Cell Institute was the first in the nation to take an interdisciplinary approach to the burgeoning field of stem cell science. “Minnesota was on our radar as one of the places that had made a strong commitment to stem cell research,” recalls U of M cardiac researcher Doris Taylor, Ph.D., a Duke University faculty member at the time.

Progress was stymied nationally, however, when the government severely restricted federal funding for human embryonic stem cell (hESC) studies, and the science itself proved extremely difficult to master.

But today, as the Stem Cell Institute marks its first decade, another “medical revolution” is taking place, says John E. Wagner, M.D., clinical director of research at the institute and director of the blood and marrow transplant program in the Department of Pediatrics. Fueling that revolution are promising new discoveries using stem cells — embryonic stem cells, which have become more available under revised federal guidelines, as well as stem cells from skin, bone marrow, and umbilical cord blood.

Housed just a stone’s throw from the new football stadium in the McGuire Translational Research Facility, the Stem Cell Institute is drawing on expertise from across the University to launch its next decade of discovery. The state-of-the-art facility — anchor to the University’s emerging Biomedical Discovery District — was made possible in large part by a $10 million gift from the William W. and Nadine M. McGuire Family Foundation that also triggered state bonding.

The facility is at the core of our discoveries, says Stem Cell Institute director Jonathan Slack, Ph.D., F.Med.Sci. “But the wider group of 32 labs across campus is also essential for our continued success.”

Unprecedented opportunity

It’s well known that all stem cells share an ability to reproduce themselves and to differentiate into specific cell types. What’s shaken up the field lately is a monumental discovery that occurred in 2006. Researchers in Japan announced that they had taken a handful of genes and turned an ordinary skin cell backward in its development until it became an undifferentiated stem cell.

Known as induced pluripotent stem cells, or iPS cells, they present an unprecedented opportunity. They come from a plentiful, easy-to-obtain source — skin — and they’re not controversial in the way that embryonic stem cells have been.

One of Slack’s first actions was to set up a facility to introduce iPS technology to Minnesota. Led by research associate James Dutton, Ph.D., the Stem Cell Institute has made a number of new human and mouse iPS cell lines and has helped several other groups at the University make their own iPS cells.

Meri Firpo, Ph.D.

Meri Firpo, Ph.D., an assistant professor of endocrinology, is at the forefront of this new technology. Recruited by the University four years ago to investigate stem cell treatments for type 1 diabetes, she is working to develop transplantable, insulin-secreting cells.

The University has a world-renowned program in pancreas cell transplantation, but cells from donor cadaver organs are in short supply, and transplant patients are at risk of suffering an adverse immune response. Now, with iPS technology, Firpo hopes to develop productive islet cells that work in humans and sidestep the rejection problems inherent in transplantation.

“Stem cells provide another potential source of islets for transplantation and offer us tremendous potential to conquer this complicated disease,” says Firpo, whose research got a major boost from a $40 million pledge made last December by the Richard M. Schulze Family Foundation to a group of University scientists aiming to develop a cure for type 1 diabetes.

A powerful weapon

For Dan S. Kaufman, M.D., Ph.D., associate director of the Stem Cell Institute, iPS cells offer a new take on another difficult challenge. Trained in hematology and immunology, Kaufman completed his postdoctoral work at the University of Wisconsin- Madison in the very lab where human embryonic stem cells were first isolated. Indeed, while at Wisconsin, he was the first to produce blood cells from hESCs.

Dan S. Kaufman, M.D., Ph.D.

Now Kaufman is investigating the use of iPS cells to create hematopoietic stem cells, the blood-reconstituting cells found in bone marrow and cord blood, to be used in such therapies as bone marrow transplants to treat patients with leukemia, lymphoma, myeloma, and other cancers. He’ll compare the effectiveness and efficiency of using iPS cells with using embryonic stem cells to derive blood cells suitable for these therapies.

That does not mean that Kaufman has closed the door on embryonic stem cells. In fact, he recently turned hESCs into disease-fighting natural killer (NK) cells that are able to completely eliminate human leukemia cells when transplanted into a mouse model. His dramatic results showed that the hESC-derived NK cells were significantly more potent killers of cancerous tumor cells than other NK cell populations tested, including those derived from umbilical cord blood. He also has shown that the hESC-generated NK cells are highly effective in killing breast cancer, prostate cancer, testicular cancer, and brain tumor cells. Kaufman believes that iPS cell technology holds potential for generating NK cells from a patient’s own cells. But work along those lines only intensifies research on hESCs, he says, because in order to coax iPS cells to differentiate into mature NK cells, researchers will need to know much more about how “the real McCoy” does it.

“Human embryonic stem cells provide the gold standard against which to compare iPS cells,” Kaufman says. “We want to use all available avenues to determine the optimal source of cells to treat cancer.”

John E. Wagner, M.D.

Damage repair

John Wagner and colleagues Jakub Tolar, M.D., Ph.D., and Bruce Blazar, M.D., were the first to demonstrate that stem cells found in bone marrow can repair skin. In a rare but devastating skin disease called epidermolysis bullosa, in which the skin continuously blisters and scars, these stem cell have been shown to “home” to the skin and replace the missing protein collagen 7 that anchors the skin to the body.

“This is the first time ever that stem cells have repaired an extracellular matrix disease, and the implications for the treatment of many diseases are substantial,” says Wagner, who holds the Children’s Cancer Research Fund Hageboeck Chair in Pediatric Cancer Research and the McKnight Presidential Chair in Hematology and Oncology.

Changing the world for people with diseased hearts, or “reversing aging” is what occupies Doris Taylor, now director of the University’s Center for Cardiovascular Repair. She and her team have started their search with repairing the heart and more recently investigated the use of bone marrow stem cells in treating plaque buildup in animal models of atherosclerosis and found that the cells can reverse blood vessel damage. They have also shown that stem cells differ in men and women and that those differences may begin to explain why men develop heart disease earlier than women.

Taylor also is interested in exploring the “nature vs. nurture of stem cells,” and she has just the tool to investigate that question. She and her lab made news around the world last year when they used a detergent to rinse away the heart cells from a cadaver rat heart, leaving behind the extracellular matrix. On the remaining scaffold, the team then rebuilt beating muscle and blood vessels.

Since stem cells respond to cues from the environment they’re introduced to, researchers can use that extracellular matrix to understand how a stem cell perceives its mission. “Does it know where it came from,” Taylor poses, “or does it know what it should be?” The tool may also reveal whether stem cells act differently when introduced to an area where injury, like a heart attack, has occurred. By altering genes and cell markers, “we can learn what it takes to rebuild functioning tissue,” she says.

Taylor, who holds the Medtronic-Bakken Chair in Cardiovascular Repair, believes chronic disease and aging are basically failures of the body’s stem cells and also is working with her team to develop stem cell approaches to repair early aging-related injury.

Walter Low, Ph.D.

Walter Low, Ph.D., professor and associate head of research in the Department of Neurosurgery, is working on tissue repair, too — in the brain. He and his team discovered a type of stem cell within human umbilical cord blood that has properties of multipotent stem cells (which can form cells of many kinds of tissue), and they are investigating whether these cells can restore brain tissue following an ischemic stroke, ultimately improving limb mobility.

They are also taking a close look at stem cells that cause damage rather than repair it. Two years ago, Low and John Ohlfest, Ph.D., assistant professor in the Department of Neurosurgery, identified and characterized mutated neural stem cells that are capable of causing brain tumors. These socalled cancer stem cells or brain tumor stem cells are the source of the selfrenewing cells within tumors, explains Low, who holds the Fesler-Lampert Chair in Aging.

The researchers developed a brain tumor vaccine that could destroy brain tumor stem cells, and recently, they obtained FDA approval to launch a phase 1 clinical trial to determine the safety of their brain tumor vaccine for patients with glioblastoma multiforme — a dire prognosis. The vaccine may eradicate the malignancy and, Low hopes, “other types of cancers where cancer stem cells are the source of the tumor.”

Jonathan Slack, Ph.D.

An eye to the future

The diversity of such top-level expertise throughout the University will ensure that the Stem Cell Institute remains internationally competitive over the next decade, notes Slack, holder of the Edmund and Anna Marie Tulloch Chair in Stem Cell Biology.

Slack, who came to Minnesota two years ago from Britain’s University of Bath, is internationally known for his discovery of the molecular cues that control embryonic development. His more recent work has focused on the basic science of regeneration — and specifically on how tadpoles can regrow the muscle and spinal cord of injured tails and the mechanisms whereby one cell type can change into another.

As the institute’s director, Slack is forging partnerships with scientists not only across the University but also beyond its walls. The Stem Cell Institute is working with researchers at the University’s Lillehei Heart Institute and the University of Wisconsin- Madison, for example, to study heart and blood progenitor cells to learn more about normal heart and blood development and investigate possible therapies using the progenitor cell populations.

Slack has also worked with University neurology professor John Day, M.D., Ph.D., director of the Paul and Sheila Wellstone Muscular Dystrophy Center, and scientists at the Katholieke Universiteit Leuven in Belgium to create a pig model of muscular dystrophy that will enable more accurate studies of cell therapy to treat the disease.

Other key partners include the Blood and Marrow Transplant Program and the University’s Molecular and Cellular Therapeutics Facility, which has the capability to grow large numbers of cells and the expertise to translate stem cells and their derivatives into therapies for patients.

“This is a very exciting moment,” Slack concludes. “The future of cell therapy is really limitless.”

By Kate Ledger

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