In 2000, when the University of Minnesota launched its Stem Cell Institute, a small group of researchers came together to plot the map in a new realm of science.
Twenty years later, the U’s Stem Cell Institute — the first interdisciplinary, academic institute in the United States — has grown greatly in size and impact. Today,
53 researchers from 22 departments across the University continue that trend, making discoveries that bring hope to patients facing some of the world’s most common but complex diseases.
“You know, 20 years is not that long, and it’s staggering to see the scientific advancements that have occurred in such a short time span,” says the institute’s director, Brenda Ogle, Ph.D. “What really gets me excited is to see the realization of a promise, and that promise is coming in the way of therapeutics. But it’s also coming in the way of understanding human health and disease in a way that we couldn’t have without stem cells.”
The U of M Medical School established itself as a leader in stem cell research more than five decades ago. In 1968, Medical School immunologist Robert A. Good, M.D., completed the world’s first successful bone marrow stem cell transplant between two people who were not identical twins. The procedure saved a young boy with a severe immune system deficiency from certain death.
By the 1980s, Medical School hematologist Philip McGlave, M.D., had achieved a new milestone, transplanting stem cells from unrelated donors’ bone marrow to treat cancer. It put hematopoietic stem cell transplantation on an international stage, catching the eye of Belgian clinician Catherine M. Verfaillie, M.D., who later traveled to the Medical School to study under McGlave. She eventually became the Stem Cell Institute’s first director.
Year after year, researchers at the U and around the world continue to gain new knowledge that further reveals the promise of stem cells. Today, scientists can grow human cells and tissue outside the body, forging new pathways to study normal function, disease processes, and therapeutic potential for regenerative medicine. Here are a few of the ways the U’s stem cell experts are working to turn that potential into reality.
Replacing damaged heart muscle
Brenda Ogle, Ph.D.
Director, Stem Cell Institute
As we age, our hearts naturally grow weaker, but cardiovascular diseases and conditions accelerate that process. Everything from coronary artery disease to high blood pressure takes a toll on our tickers.
“When cardiac muscle cells die, they aren’t replaced by the body,” says Ogle. “What you end up getting instead of new muscle is a scar, and it cannot actually contract like a muscle cell. It’s more like a structural Band-Aid.”
Ogle’s lab uses stem cells to grow new heart tissue in a petri dish to replace lost cardiac muscle. Her team uniquely organizes the cells, ensuring the new tissue patch beats in rhythm with the rest of the heart.
Currently, Ogle’s heart patches are being 3D-printed and tested at the University of Alabama-Birmingham. In preclinical studies, the patches are both recovering function of the heart and avoiding arrhythmia, she says.
Ogle also applies her “heart in a dish” concept to create first-of-their-kind human heart models that scientists can use to test drugs and medical devices.
“A lot of therapy testing has to be done in animals. That’s problematic, not only because we’re utilizing the animals themselves, but also because it’s never a human system,” Ogle says. “By using this framework, we now have a model system where we can test therapies prior to testing on humans.”
Healing skin wounds
Jakub Tolar, M.D., Ph.D.
Dean, Medical School; vice president for clinical affairs, University of Minnesota;
former director, Stem Cell Institute (2013–19)
Considering how much pain can come from the tiniest paper cut or burn, imagine how devastating large skin injuries can be.
In 2007, Tolar began working with patients who have a severe skin blistering disorder — recessive dystrophic epidermolysis bullosa (RDEB) — that results in chronic and life-altering wounds. The first line of therapy Tolar tried was the prototypical stem cell therapy, bone marrow transplantation. While some patients saw improvement, chronic wounds persisted.
By 2016, Tolar had joined forces with Michael McAlpine, Ph.D., holder of the Kuhrmeyer Family Chair in Mechanical Engineering, to develop a skin-replacement therapy for any severe skin wound. They are now collaborating on an ambitious project to create custom skin grafts using 3D-printing technology. The skin cells used in the printing process are made from induced pluripotent stem cells, which can be cultured from patient cells collected via a small skin punch.
“Most of us take our skin for granted,” Tolar says, “but it forms the external boundary of who we are. Being able to produce the complex layers of the skin without causing the damage of harvesting a graft would allow us to speed healing and protect patients from infection, dehydration, pain, and other dangerous complications of skin injury and loss.”
In addition to helping people who have RDEB, these 3D-printed skin grafts could greatly improve outcomes for those who have injuries and conditions requiring reconstructive surgery, chronic skin ulcers (like those from diabetes), and severe burns.
Targeting macular degeneration
Deborah Ferrington, Ph.D.
Distinguished McKnight University Professor, Department of Ophthalmology and Visual Neurosciences
Imagine the center of your vision getting worse and worse until you can no longer read, drive, or recognize faces.
That is the frightening progression of age-related macular degeneration (AMD), the leading cause of vision loss among people ages 55 and older in the developed world.
There is no effective treatment or cure for dry AMD, the most common form of AMD in the United States. Animal models of the disease, in lab mice, for example, cannot replicate the peculiarities of the human eye, making drug testing difficult, says Ferrington, holder of the Elaine and Robert Larson Endowed Vision Research Chair.
But Ferrington and James Dutton, Ph.D., the director of the Stem Cell Core at the Stem Cell Institute, are working to uncover new ways to treat dry AMD. Their team collects cells from the conjunctiva — the cells covering the white of the eye — in routine biopsies from AMD patients. The scientists grow these cells and reprogram them into induced pluripotent stem cells that are then directed to become retinal pigment epithelium cells — the very cells that die in dry AMD.
“It allows us to test drugs in the specific cell that we want to deliver those drugs to,” Ferrington says.
The drugs they are testing are approved by the U.S. Food and Drug Administration for other conditions, she adds, so any effective drugs they identify may be fast-tracked for patient use.
“This could actually be transformative for medicine and for the treatment of patients with AMD,” Ferrington says. “We are still at the proof-of-principle stage right now. But this is an important first step.”
Generating cells in a dish to treat MD
Rita Perlingeiro, Ph.D.
Professor, Department of Medicine
Can stem cells generated in a petri dish treat muscular dystrophy? Fast-moving research by Perlingeiro suggests the answer is yes.
Her lab has successfully transferred stem cells from a healthy donor into mice that model the genetic neurodegenerative disease — and her team has shown that these stem cells develop into functioning muscle cells that resemble normal muscle cells.
There’s more: The healthy stem cells also may outcompete the genetically defective cells, potentially replacing them in the long run. This might be possible because transplanted stem cells can seed specific regions of the muscle tissue, where they remain quiescent until they are activated to produce working muscle cells.
The research is now evolving quickly, says Perlingeiro, who holds the Lillehei Professorship in Stem Cell and Regenerative Cardiovascular Medicine. Her lab will begin work on manufacturing clinical-grade stem cells later this year. Next up is a Phase I safety trial in people who have muscular dystrophy.
Although she has focused most of her attention on Duchenne and limb-girdle muscular dystrophy, the most common forms of this genetic group of diseases, Perlingeiro says cell-replacement therapies like this one hold great promise for treating any kind of muscular dystrophy, regardless of the underlying genetic defects.
“If this approach proves successful,” she says, “this may mean new effective treatments for patients suffering from these devastating diseases.”
Healing spinal cord injuries
Ann Parr, M.D., Ph.D.
Associate professor, Department of Neurosurgery
Spinal cord injuries often leave patients paralyzed and numb in their extremities. They also cause problems with blood pressure, leg spasticity, bowel and bladder control, erectile function, and fertility.
“These patients have so many issues,” says Parr, director of spinal neurosurgery, with a lab in the Stem Cell Institute. Unfortunately, she says, there are no good therapies for many spinal cord injuries.
Parr hopes to change that by engrafting stem cells to damaged spinal cords to restore lost neural circuitry.
With Dutton, Parr developed a protocol to program stem cells to become spinal neurons in a swift five days. Says Parr, “I don’t think anybody makes these cells as well as we do.”
Then Parr teamed up with McAlpine, the mechanical engineering professor, to create scaffolds of silicon and live spinal cord precursor cells. Parr inserts these tiny scaffolds into lab rats that have severed spinal cords. The 3D-printed cells develop quickly, form neural networks, and even extend axons to the brain. The regenerating cells communicate among themselves and with native neurons.
Next, Parr will find out whether the rats can actually regain function. She hopes that one day her lab can help humans with spinal cord injuries do the same.
Restoring one’s ability to walk would be a “home run,” she says, but mere base hits such as helping patients regain control of their bowels or move their arms would be huge. Says Parr, “Even small gains can be meaningful.”
Killing cancer stem cells
Masato Yamamoto, M.D., Ph.D.
Professor, departments of Medicine and Surgery
Many scientists nurture and coddle stem cells as though they were cultivating orchids. Not Yamamoto.
“We are trying to kill them!” he says.
The cells that most interest Yamamoto are cancer stem cells, which serve as the seeds of cells that form problematic tumors. Yamamoto calls them “cancer-initiating cells,” as they cause cancer to recur and spread after surgery.
In his lab, Yamamoto, a member of the Masonic Cancer Center who holds the Eugene C. and Gail V. Sit Chair in Pancreatic and Gastrointestinal Cancer Research, isolates cancer stem cells from tumor samples. Then, from a diverse sample of more than a billion adenoviruses, he selects a virus with the ability to invade the cancer stem cells, proliferate, and kill the cancer cells.
Today, people facing colon cancer, even after undergoing surgery, frequently see the cancer recur and spread to the liver. In Yamamoto’s mouse studies, treatment with select viruses inhibited the recurrence of tumors — the basis, perhaps, for a medical therapy that would prevent the recurrence of cancer in humans after surgery, too.
“That makes the patient happy,” Yamamoto says, “and that makes the surgeon happy.”