With Focus on Skin Cells, University of Toronto’s Michael Sefton Seeks “Big Step” in Diabetes Treatment

Can dendritic cells in the skin be an important piece of the puzzle for enabling stem cell transplants for diabetes?

Michael sefton, a renowned tissue engineer from the University of Toronto, is confident enough that with the support of JDRF type 1 diabetes nonprofit, he is about to launch a major new chapter of his research.

The work will build on a discovery by a research team from the University of Alberta in 2000 that proved that cells in the islets of Langerhans (also called islets of Langerhans), which produce insulin and are found in the pancreas, could be transplanted from a donor into the liver of people living with type 1 diabetes. Treated patients saw their diabetes disappear for long periods of time and no longer needed an injection. ‘insulin. The procedure became known as the Edmonton Protocol.

“It was a huge discovery of this group,” said Sefton, executive director of Medicine by Design and university professor in the Department of Chemical Engineering and Applied Chemistry and the Institute of Biomedical Engineering in the Faculty of Applied Sciences. and engineering. “But the problem was the liver. It was a hostile environment for these new cells and triggered an immune response that killed many of them and the patients’ diabetes eventually returned. ”

Nonetheless, it got Sefton thinking: What if there was a better place to implant the cells?

He thought of the skin. Research has proven that the skin – or just underneath – is an area less likely to be hostile to transplanted cells such as pancreatic cells. Not only that, but implanting cells under the skin is less invasive than doing it in the liver. The cells could be recovered more easily, which could make the therapy safer for the patient

But the method posed another problem. The skin has too few blood vessels for implanted cells to survive and the body to manage blood sugar. Could scientists find a way to create blood vessels?

In 2016, JDRF awarded Sefton over $ 1 million to explore the possibility. To create the blood vessels, Sefton’s team used a material containing methacrylic acid (MAA).

“Once we insert a polymer gel with MAA under the skin, the MAA interacts with the living system in the body (mice are currently used) and it creates the blood vessels,” says Sefton. “We are just starting to understand how the MAA works. And it allows the implanted pancreatic cells to deliver insulin throughout the body to do its job of controlling blood sugar levels and thus stop the diabetic state.

Another major hurdle was getting enough pancreatic cells for transplantation. Sefton, whose lab is located at the Donnelly Center for Cellular and Biomolecular Research, said about one million pancreatic islets (each islet contains about one thousand cells) are needed for each patient treated via the protocol’s template. Edmonton. The acquisition of islets often required two donors.

But now, says Sefton, scientists love Maria Cristina Nostro, who is also a Medicine by Design-funded scientist, can create insulin-producing cells from stem cells, which provides an unlimited supply.

With those big issues resolved, the team has yet another to deal with: the immune response the body develops when new pancreatic cells are transplanted.

The body’s natural response is to reject, say, a new heart or kidney. It is the body that attacks what it perceives to be an invader, in the same way that the immune system attacks harmful bacteria or viruses that have entered the body.

While, as Sefton says, the skin tends to react differently than the liver, there will always be a response that tries to reject the transplanted pancreatic islets once implanted.

This is where Sefton believes dendritic cells can play an important role.

Discovered by German pathologist Paul Langerhans (the same scientist who also discovered the pancreatic islets that bear his name) in 1869, dendritic cells are powerful immune cells found in the skin.

“They will, of course, mount an immune response once we implant the pancreatic islets,” Sefton said. “But we believe MAA has properties that will work on dendritic cells in the skin to be tolerant of pancreatic cells. We don’t want to suppress the immune system because it’s dangerous for the patient.

“We want to trick him into accepting the new pancreatic cells as if they were part of the patient’s body. And if we can do it, we will have taken a big step forward. ”

Sefton and his team will use the new JDRF grant over the next two years to continue to explore this intuition.

Adventurous research in the health sciences is nothing new for Sefton, who set a record for innovation in biomedical research that has earned him worldwide respect.

He was appointed university professor in 2003, the highest honor bestowed by the University of Toronto on its faculty. In 2017, he was honored with the Order of Canada for his leadership in biomedical engineering. Prior to joining Medicine by Design, he was Director of the Institute of Biomedical Engineering at the University of Toronto and has many scientific achievements as a scientist, including being among the first to combine living cells with polymers and to effectively launch the field now called tissue engineering.

Today, as executive director of the Medicine by Design strategic research initiative, Sefton speaks with pride and enthusiasm about the work of scientists tackling difficult health issues using regenerative medicine, a branch of health research and treatment that has exploded globally since stem cells were discovered by scientists at the University of Toronto James till and Ernest McCulloch in 1961.

“The hallmark of our approach is the convergence of scientists from a multitude of disciplines from the University of Toronto and our nine partner research hospitals,” he says. “We have biologists, biochemistry experts, physicists, engineers and specialists in all aspects of medicine working together and sharing ideas. Our goal is to think far beyond the obvious and act boldly to find ways to improve treatments and possibly even cure major illnesses. ”

Medicine by Design was founded in 2015 with $ 114 million from the Canada First Research Excellence Fund. Projects in Medicine by Design’s portfolio focus on using stem cells as living therapies, harnessing the body’s repair capacity, disabling disease triggers, and creating technologies to advance regenerative medicine. .

In this exploration list, Medicine by Design research teams are advancing in the treatment of a multitude of diseases such as restoration of vision lost due to age-related macular degeneration, cell use strains to treat diseased livers in patients who have no hope of a liver transplant, stop dangerous and difficult to diagnose abdominal aortic aneurysms before they cause their damage, and create methods to help the brain to self-repair after a stroke.

“We place great importance on new ideas and risky research,” says Sefton. “That’s how you have to think when you really want to change things. I want people to hear about our work and think that what we are trying to achieve is impossible. I firmly believe that when it comes to illness, we should not just accept what nature gives us with, for example, cancer, stroke or diabetes. We can do better than nature.

He also stresses that technological advancements are essential to enable breakthroughs. He emphasizes the importance of tools like CRISPR, a powerful gene editing technology that won the Nobel Prize for Emmanuelle Charpentier and Jennifer Doudna in 2020 for creating opportunities that were unthinkable even 30 years ago.

“That’s why I’m saying that in 30 years regenerative medicine will be at the center of how we treat disease,” says Sefton. “It will be standard practice and it will give us a level of health that we never thought possible.

“We might even be able to eliminate many diseases. ”


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