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At 62, Oscar Campanini expected some aches and pains in his joints, especially after his weekly pickup soccer game. But two years ago, the pain in his knees became so overwhelming he could barely walk. Because both knees had been surgically mended previously, doctors said he had two choices: periodic cortisone injections or total knee replacements.

“I wasn’t happy with either of those options,” he says.

On a visit to Mayo Clinic’s Florida campus, he met with Shane Shapiro, M.D., who specializes in sports medicine and musculoskeletal pain. Dr. Shapiro told Campanini he was eligible for the first-ever randomized clinical trial exploring the safety of stem cells for arthritis.

Despite limited research, many types of stem cell injections are offered worldwide. But at Mayo Clinic, the first step was to conduct research.

“We weren’t comfortable offering this as a treatment to patients until we or someone else had studied it in a rigorous fashion,” Dr. Shapiro says.

Campanini entered the trial and received two injections: his own bone marrow-derived stem cells in one aching knee and a placebo of saline solution in the other.

Stem cell mystery

The results, published in the American Journal of Sports Medicine, showed the cells didn’t cause any serious problems for participants. But another finding surprised the researchers.

Patients reported pain relief in both knees ─ even the one that received only saline. The mysterious results appeared distinct from a placebo effect, Dr. Shapiro says, since patients were aware only one knee was receiving cells (they didn’t know which one). And while many patients found their aches eventually returned, the pain-free period lasted from a few months up to more than two years ─ longer than placebos would typically work.

“We’re still studying the mechanisms,” Dr. Shapiro says.

The study adds to a rapidly expanding field that takes a new approach to treating disease: restoring health by replacing, repairing or regrowing damaged or degenerating tissues in the body.

Shane Shapiro, M.D., and Andre Terzic, M.D., Ph.D., the Marriott Family Professor and Director of Comprehensive Cardiac Regenerative Medicine and the Michael S. and Mary Sue Shannon Family Director of the Center for Regenerative Medicine

Mayo embraced this field of regenerative medicine and already has achieved several firsts, notes Andre Terzic, M.D., Ph.D., head of Mayo Clinic’s Center for Regenerative Medicine.  A team on Mayo Clinic’s Florida campus was first to use stem cells in humans to research lung transplant care. Another team in Minnesota researched using stem cells in pediatric congenital heart disease. A group in Arizona is first to populate a scaffold with stem cells to rebuild a larynx. When Mayo researchers gathered to share their work in regenerative approaches, the schedule boasted more than 60 presentations.

Mayo also is the first to offer an advanced degree program in regenerative medicine sciences.

Cutting Across Traditional Pathways

Stem cells have the potential to reinvent treatment across specialties. For example, Alison Bruce, M.B, Ch.B., a Mayo Clinic dermatologist, is exploring the use of platelet-rich plasma, concentrated growth factors from blood, to stimulate hair growth in women who have female-pattern baldness. And another clinical study is exploring the use of stem cells from body fat to treat pressure wounds.

“We’re asking Mayo physicians in other specialties to point out which medical conditions are very difficult to treat and that might be addressed by these emerging therapies,” Dr. Shapiro says.

Abba Zubair, M.D., Ph.D., a researcher on Mayo Clinic’s Florida campus, has long been investigating the role of stem cells in bone marrow transplantation. But after his mother died of stroke several years ago, he focused on using stem cells to treat brain injury. He and Mayo collaborators in neurology researched mouse models of stroke and found that an infusion of stem cells helped regenerate neurons and blood vessels.

Guojun Bu, Ph.D., a Mayo Clinic neuroscientist, specializes in Alzheimer’s disease. He was recruited to Mayo Clinic partially for his expertise in creating workable engineered stem cells, known as induced pluripotent stem cells or iPSCs. Developed by Shinya Yamanaka, a Japanese Nobel laureate, the technology involves taking ordinary cells — from skin biopsies, for example— adding four transcription factors to the mix, and reprogramming the cells backward along their developmental pathway into functional stem cells.

Alison Bruce, M.B., Ch.B.; Abba Zubair, M.D., Ph.D.; Guojun Bu, Ph.D., the Mary Lowell Leary Professor of Medicine and the Jorge and Leslie Bacardi Associate Director of the Center for Regenerative Medicine

“The iPSCs resemble almost exactly the embryonic stem cells, which means they have unlimited potential to proliferate, and also the potential to differentiate or become any cell type in the body,” Dr. Bu explains.

In the Neuroregeneration Laboratory he directs, Dr. Bu has established nearly 300 lines of iPSCs from patients and their families who have contributed cells to further brain research. The iPSCs undergo rigorous quality controls and are available to researchers across the campus. In particular, the lab aims to use iPSCs to develop various brain cell types, including neurons and support cells known as glial cells that are destroyed in neurodegenerative disease. Dr. Bu’s team has begun building 3-D models of brains, including various brain cells and blood vessels to study disease pathways and test new drugs.

“We could take patient cells and potentially do gene editing to correct a genetic mutation,” Dr. Bu explains. “With the correction, we could conceive of making the cells into brain cells that have been lost and then one day potentially transplanting them back into the patient.”

Stem Cells as Healing Forces

 The lab of Alfredo Quiñones-Hinojosa, M.D., a Mayo Clinic neurosurgeon, has long been focused on cell migration, which helps in understanding how aggressive brain tumor cells penetrate healthy tissue. But he’s also applied his interest in migration to stem cells. Recently, his group found that stem cells in the fetal brain respond to molecular cues to migrate from their source to the olfactory bulb, the brain area related to our sense of smell.

In this way, stem cells also may help treat brain tumors. His group is investigating genetically altering the cells or using them to carry a nanoparticle, because the cells have the capability to track down cancer cells.

“We don’t know how, and we don’t know why, but they track tumors and act like special forces — like Trojan horses — and we can use them to deliver therapy right to the cancer,” says Dr. Quiñones-Hinojoa. In collaboration with Johns Hopkins, Dr. Quiñones’ team is studying stem cells that carry a protein that converts malignant cell types like glioblastoma cells into treatable cells.

However, it’s not just the stem cells that may be useful therapeutically. The lab of Tushar Patel, M.B. Ch.B., a Mayo Clinic hepatologist, is studying tiny pouches of molecules — proteins, RNA and some DNA — released by stem cells.

They’re known as extracellular vesicles. And when they emerge from stem cells, they seem to encourage healing. His group is exploring their effect on liver injuries, including acute liver failure. In experimental models liver failure is fatal to mice. However, when the vesicles were applied in the mouse models, nearly 60 percent survived.

“We did the experiment over and over,” says Dr. Patel. “We just couldn’t believe it.”

Alfredo Quiñones-Hinojosa, M.D., the William J. and Charles H. Mayo Professor; and Tushar Patel, M.B., Ch.B., the James C. and Sarah K. Kennedy Dean of Research, Mayo Clinic Florida

His group also has explored whether extracellular vesicles can reduce the potentially dangerous inflammation that occurs when livers are reconnected to blood vessels aftersurgery or transplant. In mouse models, they found liver enzymes indicating injury dropped to near normal levels and dead tissue was reduced from 50 percent to 5 percent.

Dr. Patel says, “Our hope is that extracellular vesicles might become a tool to improve a donated organ and increase the number of livers available to patients.”

But with this hope comes the knowledge that much work remains to be done.

Each Mayo campus has a regenerative medicine consult service for discussions with patients. The technologies and applications continue to expand.

“Patients are asking for stem cell therapies. They’ve certainly heard about them, sometimes they’ve heard hype,” Dr. Shapiro acknowledges. “We have to tell our patients we don’t have all the answers yet. We’re at the stage where we’re ready to discover, translate and apply what we learn.”

– Kate Ledger, January 8, 2018