Stem Cell

Researchers working on injection-free cell therapy for diabetes

Christopher.Sorensen — Fri, 17 Dec 2021 20:40:18 +0000

Researchers working on injection-free cell therapy for diabetes

Christopher.Sorensen Fri, 12/17/2021 - 15:40

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Juan Carlos Zúñiga-Pflücker and Sarah Crome are among the researchers working on generating pancreatic cells that can be transplanted to diabetes patients without being destroyed by their immune systems (photos courtesy of Medicine by Design)

Julie Crljen

Topic

Our Community

Institute of Biomedical Engineering

Insulin 100

Princess Margaret Cancer Centre

Sunnybrook Health Sciences

Temerty Faculty of Medicine

Toronto General Hospital

Resarch & Innovation

Medicine by Design

Stem Cell

University Health Network

In a person with type 1 diabetes, the body mistakenly attacks pancreatic cells that produce insulin, a hormone responsible for regulating blood sugar.

Without insulin, serious and eventually fatal symptoms will occur. Yet, imagine if, instead of needing daily insulin injections, people with diabetes could have insulin-producing cells placed back into the body, fixing the problem at its source. This is the vision of a Medicine by Design-funded research team.

The approach is not without its challenges.

“Scientists are able to generate pancreatic cells from stem cells in the lab, and they can be transplanted to someone who has lost pancreatic function, but they’ll be reattacked by the immune system,” says Juan-Carlos Zúñiga-Pflücker, senior scientist at Sunnybrook Research Institute and professor of immunology in the Temerty Faculty of Medicine. “What our work is meant to do is enable those transplants to be broadly acceptable so anyone can benefit from transplanted therapies. But the barrier of the immune system is a difficult thing to overcome, and even more so in the context of autoimmunity.”

The cells are attacked because the immune system recognizes them as harmful invaders instead of helpful therapies. It is a complex problem that demands a complex strategy – and that strategy is an emerging area of research called immunoengineering, which uses bioengineering techniques to manipulate the immune system.

The only way to currently suppress the immune system is through drug treatments, but they’re not selective; they suppress the whole immune system and leave people vulnerable to infection and illness.

The team’s strategy aims to be more precise. They want to finely tune the immune system to maintain a healthy system while not rejecting a therapeutic transplant.

Zúñiga-Pflücker says a collaborative effort is important in solving this major challenge to regenerative medicine. “We can optimize cell types and engineer effective tissues in our separate labs. But if we don’t come together to create better tools to engineer the immune system, these therapies will not be usable. It’s something very fundamental.”

The team is one of 12 sharing nearly $21 million in funding from Medicine by Design over three years. Funded by a $114-million grant from the Canada First Research Excellence Fund, Medicine by Design is a strategic research initiative that is working at the convergence of engineering, medicine and science to catalyze transformative discoveries in regenerative medicine and accelerate them toward clinical impact.

Though the research could be applied broadly across regenerative medicine therapies, type 1 diabetes makes an ideal test case, says Zúñiga-Pflücker, who is also chair of the department of immunology.

“Not only is diabetes an autoimmune disease, where the diabetic’s own immune system attacks and kills insulin producing cells, but attempts to replace the lost cells with transplanted cells are also challenged by other impacts of the disease, as well as the presence of auto-reactive immune cells,” he says. “This makes it a powerful test case for our research since we can test the transplants under multiple immune stresses.”

Zúñiga-Pflücker leads the project, which brings the work of six different labs together.

Two labs, led by the Temerty Faculty of Medicine’s Maria Cristina Nostro, a senior scientist at the University Health Network’s (UHN) McEwen Stem Cell Institute; and Sara Nunes Vasconcelos, a scientist at UHN’s Toronto General Hospital Research Institute, are using stem cells to generate tissues containing insulin-secreting cells for transplants.

Zúñiga-Pflücker says that this arm of the project is well ahead of schedule. “The Nostro and Vasconcelos labs are defining the right conditions that are necessary for generating insulin-producing cells, which are called islet cells. They’re creating newer and more effective ways to make these tissues.”

Nostro and Vasconcelos are also associate professors at U of T in the department of physiology and Institute of Biomedical Engineering, respectively.

The tissues created in their labs will be used to test the work of the other four labs involved in the project, which are concerned with engineering the immune reaction. And here, each of these labs is bringing a piece of the puzzle.

Read about research into therapeutic cell “cloaking”

Zúñiga-Pflücker and Naoto Hirano, a senior scientist at Princess Margaret Cancer Centre and a professor of immunology at U of T, work on producing regulatory T cells (Tregs). These cells can supress immune response and play a role in preventing autoimmune diseases like diabetes.

In earlier Medicine by Design-funded research, Zúñiga-Pflücker and Hirano came up with a method for producing T cells in a defined way. Some of the key breakthroughs developed as part of this research helped lay the foundation for Notch Therapeutics, a company co-founded by Zúñiga-Pflücker, which closed an $85-million (U.S.) Series A financing earlier this year.

Now, in the current research project, the two labs are crafting methods for producing Tregs and investigating how harnessing the power of other types of immune cells to work alongside the Tregs can induce the immune system to tolerate transplanted therapies.

The third investigator is Tracy McGaha, whose lab is looking at the role of macrophages, a type of white blood cell that that typically helps to attack foreign substances but can also play a role in repairing damaged tissues. McGaha is a senior scientist at Princess Margaret Cancer Centre, UHN, and a professor in the department of immunology in the Temerty Faculty of Medicine.

A fourth lab, led by Sarah Crome, is investigating a family of immune cells called innate lymphoid cells (ILCs), which act within tissues to help induce and modulate immune responses.

“We know several immune cell populations we individually study can protect from harmful immune responses and promote immune tolerance,” says Crome, who is a scientist at the Toronto General Hospital Research Institute, UHN, and an assistant professor of immunology at U of T. “The trouble is when you get into a situation that combines an autoimmune disease with rejection that can occur following islet transplantation, it’s a real challenge shutting down multiple harmful and sustained immune responses.”

Crome says that there are many different types of ILCs, so her work focuses on narrowing down which types of ILCs are best to use along with the Tregs.

Right now, each of the four labs working with immune cells are optimizing their cell types and techniques, and then, Crome says they will bring all their “best players” together.

“We’re really looking at harnessing whole networks of cells, instead of just looking at one cell population at a time. It’s bringing all of our collective expertise together into one project that makes this a powerful approach.”

Zúñiga-Pflücker says Medicine by Design has been instrumental in uniting this team of experts.

“Thanks to Medicine by Design’s support of our immunoenigneering program, we’re able to bring together multiple research sites within the ��߲ݴ�ý and affiliated research institutes; UHN’s Princess Margaret Cancer Centre, Toronto General Hospital Research Institute and McEwen Stem Cell Institute; and Sunnybrook Research Institute.”

U of T researchers uncover stem cells' first steps on path to becoming body's organs

Christopher.Sorensen — Tue, 25 Jun 2019 20:08:39 +0000

U of T researchers uncover stem cells' first steps on path to becoming body's organs

Christopher.Sorensen Tue, 06/25/2019 - 16:08

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The researchers say the discovery could have important implications for regenerative medicine and shed new light on the development of certain types of cancer (photo by Pixabay)

Sean Bettam

Topic

Breaking Research

Cell and Systems Biology

Faculty of Arts & Science

Global

Graduate Students

Research & Innovation

Stem Cell

New research by cell biologists at the ��߲ݴ�ý provides significant new insight into the first step stem cells go through to turn into the specialized cells that make up organs.

The findings, published online in Genes & Development, implicate the ability of proteins to hang around in cells – their stability – as a major factor in controlling a stem cell’s state, and in the decision to remain a stem cell or transform into a specialized cell.

Stem cells are regulated by a network of proteins that maintain their ability to become any type of cell – a property known as pluripotency. These proteins – known as transcription factors – are produced from genes in an organism’s DNA and regulate the process by which cells decide whether to initiate development. The new findings highlight the role of KLF4, one of the transcription factors that gives stem cells their unique properties.

The study's lead author, Navroop Dhaliwal (left), recently completed a PhD with Jennifer Mitchell (right), an associate professor in U of T’s department of cell and systems biology (photo by Neil Macpherson)

“Many previous studies focus on the genes that are turned on or off as stem cells are destined to make specific organs,” says lead author Navroop Dhaliwal, who recently completed a PhD with Associate Professor Jennifer Mitchell in U of T’s department of cell and systems biology in the Faculty of Arts & Science.

“Our work exposes a situation earlier in the process where reducing gene expression by 90 per cent does not affect the amount of protein made. It was a really surprising finding when we first saw the results.”

The discovery was serendipitous as the researchers initially set out to investigate how the KLF4 gene is regulated during transcription, but soon turned their attention to the KLF4 protein instead.

The researchers found KLF4 proteins made one day remained functional 24 hours later – a particular surprise as transcription factors typically only last for two or three hours in a cell. When they looked at how stem cells differentiate and exit the stem cell state, they found KLF4 becomes unstable during the process, and by preventing this breakdown the cells can’t differentiate.

“We discovered that the KLF4 protein is highly stable and locks cells in the stem cell state,” said Dhaliwal.

“Breaking it down, however, releases stem cells to specialize and eventually become the different organs of the body.”

Dhaliwal and her colleagues say the findings indicate that KLF4 protein destabilization is a critical step in the ability of a stem cell to become any one of the hundreds of special cell types found in a mature organism.

“These findings have important implications for regenerative medicine as building new organs requires a detailed understanding of how stem cells exit their immature state,” says Dhaliwal, now a postdoctoral fellow at the Hospital for Sick Children in Toronto.

“Knowing this, we can now develop more efficient ways to produce patient-specific stem cells and differentiate these cells to more mature cells, which will be the focus of my postdoctoral work.”

Beyond its role in stem cells, KLF4 is also involved in numerous cancers. The researchers suggest the mechanisms uncovered here may shed light on its role in the development of breast cancer, squamous cell carcinoma and gastrointestinal cancer.

“The data we present highlight the importance of studying both transcriptional control and mechanisms that affect protein abundance,” says Mitchell.

“These mechanisms are particularly timely to keep in mind as more and more work shifts to a focus on gene expression using techniques like single-cell RNA sequencing, which would not have revealed the mechanisms we uncovered.”

Support for the research was provided by the Canadian Institutes of Health Research, the Canada Foundation for Innovation, the Ontario Ministry of Research and Innovation and the Ontario Graduate Scholarship program.

Bayer, Versant back commercialization of stem cell therapies in Toronto: "We go where the science is best"

ullahnor — Mon, 12 Dec 2016 18:52:24 +0000

Bayer, Versant back commercialization of stem cell therapies in Toronto: "We go where the science is best"

ullahnor Mon, 12/12/2016 - 13:52

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Professor Gordon Keller, director of the University Health Network's McEwen Centre for Regenerative Medicine and a world authority on stem cells, speaks at the announcement today at MaRS Discover District (all photos by Johnny Guatto)

Heidi Singer

Author legacy

Heidi Singer

Topic

Breaking Research

Research & Innovation

Stem Cell

Regenerative Medicine

Medicine by Design

University Health Network

CCRM

At US$225 million, it’s one of the largest investments the biotech world has ever seen – and it positions Toronto as a world leader in the development of regenerative medicine therapy, experts say.

Pharmaceutical giant Bayer AG and venture capital firm Versant Ventures today announced the creation of a company that will turn stem cell science into real-world treatments. BlueRock Therapeutics will be based in Toronto’s MaRS Discovery District, as well as in New York and Boston. The company will first work on developing new treatments for the heart and for degenerative brain disease.

“Why Canada? Why Toronto? The answer is simple,” said Jerel Davis, a managing director at Versant Ventures. “We go where the science is best.”

The four-year financial commitment is the second-largest initial investment in a startup in the history of the biotechnology industry, according to officials of Versant Ventures. The U.S.-based funders said they chose Toronto for the new firm because of the city’s strength in regenerative medicine research.

“We all know Canadian scientists are world renowned in how stem cells can be used to repair damaged tissue,” said Navdeep Bains, federal Minister of Innovation, Science and Economic Development. “The considerable investment being made now is validating that expertise.”

The investors said they were attracted to Toronto because of the regenerative medicine “dream team” of Gordon Keller and Michael Laflamme. Keller, director of the McEwen Centre for Regenerative Medicine at the University Health Network and a professor of medical biophysics at the ��߲ݴ�ý, is a world authority on stem cells. He is perhaps best known for turning embryonic stem cells into heart cells – a crucial first step in the quest to use stem cells to repair heart muscle in patients who have had heart attacks. Laflamme, a senior scientist at the Toronto General Research Institute and an associate professor in U of T's department of laboratory medicine and pathobiology, is at the forefront of developing pioneering techniques to transplant these cells safely and successfully.

“This tremendous news confirms again that the world is taking notice of the remarkable research and talent base here in Toronto, anchored by the ��߲ݴ�ý and its partner hospitals, and nurtured by key institutions such as MaRS," said U of T President Meric Gertler. "And it builds on the landmark $114-million grant through the Canada First Research Excellence Fund for our Medicine by Design project, which demonstrates the federal government’s strategic approach to supporting research clusters of truly world renown.”

Premier Kathleen Wynne and federal Minister of Innovation, Science and Economic Development Navdeep Bains were part of the announcement for the US $225 million investment in stem cell therapies for heart and degenerative brain diseases

Bains praised the initiative as a model for the kind of investment Canada wants to attract. He was joined during the announcement at the MaRS Discovery District by Ontario Premier Kathleen Wynne.

“This new venture has the potential to impact the lives of people affected by heart disease around the world,” Wynne said “I am pleased that Bayer and Versant selected Ontario to conduct this important research. It will create good jobs and economic growth, and illustrates the confidence global companies have in Ontario’s business environment and capacity for innovation.”

As one of its first priorities, the new company will work with CCRM – a Toronto-based not-for-profit that advances regenerative medicine – to create cells to rebuild muscle damaged by heart attacks and chronic heart failure. That effort will draw on Keller’s expertise creating heart muscle cells derived from stem cells.

“We have closely tracked the field of regenerative medicine for the past five years and believe the time is right to invest in stem cell therapies given recent breakthroughs in cell differentiation, manufacturing and engineering,” said Versant’s Davis.

U of T's Medicine by Design is headed by Professor Peter Zandstra (pictured at centre)

Toronto has been a centre for stem cell research starting with the 1960 identification of blood stem cells by biophysicist James Till and hematologist Ernest McCulloch, both of U of T and the Ontario Cancer Institute/Princess Margaret Cancer Centre. This discovery was instrumental in the use of blood stem cell transplants to treat diseases such as leukemia.

In the decades since the Till and McCulloch discovery, stem cells have come to be seen by scientists as potentially offering ways to treat – and perhaps cure – a host of devastating and costly illnesses such as cardiovascular disease, cancer, diabetes, blindness and neurodegenerative disorders.

In 2015, the federal government gave the ��߲ݴ�ý the largest single research award in its history – $114 million – to support Medicine by Design, an ambitious initiative led by Professor Peter Zandstra, and including cross-disciplinary researchers such as Professor Molly Shoichet to advance the design of cells, materials and therapeutics to reach this goal.

It harnesses the exceptional expertise at U of T and its affiliated hospitals and fosters unique multidisciplinary collaborations to generate new discoveries in regenerative medicine. Through strategic investments and partnerships, it is also creating a pipeline from research to commercialization that will enable Canada to realize the full value of its research advances and bring them to the world.

Medicine by Design symposium at U of T shines spotlight on regenerative medicine

ullahnor — Wed, 30 Nov 2016 22:01:59 +0000

Medicine by Design symposium at U of T shines spotlight on regenerative medicine

ullahnor Wed, 11/30/2016 - 17:01

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Nadia Rosenthal, scientific director of the Jackson Laboratory for Mammalian Genetics in Maine, and Medicine by Design Executive Director Peter Zandstra (front row) listen to a presentation at Medicine by Design’s inaugural symposium (photo by Neil Ta)

Ann Perry

Jovana Drinjakovic

Author legacy

Jovana Drinjakovic and Ann Perry

Topic

Breaking Research

Research & Innovation

Medicine by Design

Regenerative Medicine

Stem Cell

Faculty of Applied Science & Engineering

Institute of Biomaterials and Biomedical Engineering

A cannibalistic Mexican salamander that can regrow body parts lost in a fight may hold answers for researchers trying to unlock the power of stem cells to treat human disease, regenerative medicine pioneer Nadia Rosenthal told the inaugural Medicine by Design symposium held at U of T this week.

“Everything develops, but not everything regenerates,” Rosenthal, scientific director at the Jackson Laboratory for Mammalian Genetics in Maine, said as she described the Mexican axolotl’s unusual abilities, which have attracted the attention of scientists seeking to understand the basic mechanisms of regeneration.

Rosenthal was among more than 250 engineering researchers, life scientists, computational biologists, doctors and students from across the ��߲ݴ�ý and affiliated hospitals who gathered at the MaRS Discovery District on Nov. 28 to share research aimed at harnessing stem cells to treat conditions such as heart failure, cancer, liver disease and blindness.

The event, which also attracted a number of international experts in the field and representatives from the government and private sector, celebrated the first year of Medicine by Design, an initiative funded by a historic grant from the federal government’s Canada First Research Excellence Fund that is driving stem cell research from foundational discovery to real-life application through innovative collaborations.

“We are contributing something new by converging people from diverse disciplines – mathematics, the physical sciences, engineering, biology and medicine – around the big questions in regenerative medicine,” said Peter Zandstra, executive director of Medicine by Design, Canada Research Chair in stem cell bioengineering and a professor in the Institute of Biomaterials & Biomedical Engineering.

Keith Pardee, an assistant professor in U of T's Leslie Dan Faculty of Pharmacy and a Medicine by Design associate, introduces University Professor Molly Shoichet. Shoichet, a professor in U of T's department of chemical engineering & applied chemistry, spoke about bioengineering strategies in regenerative medicine (photo by Neil Ta)

“It’s a really a very exciting time for regenerative medicine in Canada,” Zandstra added. “Medicine by Design, together with the Stem Cell Network, CCRM, the Ontario Institute for Regenerative Medicine and a number of emerging regional clusters throughout the country, really represent a comprehensive innovation hub that will strengthen Canada as a leader in this emerging biotechnology sector.”

Medicine by Design, which includes more than 90 principal investigators and hundreds of graduate students and postdoctoral fellows, builds on a rich legacy of U of T contributions to regenerative medicine, beginning with the demonstration of the existence of stem cells by biophysicist James Till and hematologist Ernest McCulloch in 1960.

In its first round of collaborative team project awards, announced in August 2016, Medicine by Design awarded a total of $27 million to 20 teams across U of T and its hospital partners for projects that range from basic exploration of stem cell biology to technology development and clinical application. The initiative is also strengthening Toronto’s network of regenerative medicine researchers by recruiting emerging and established leaders in the field, and is working closely with CCRM to commercialize the breakthroughs that emerge from its research.

Read about the 20 teams chosen by Medicine by Design

“With our hospital and commercialization partners, we are building a robust pipeline from research to clinical translation to commercialization, which is moving discoveries more quickly from the lab bench to the bedside and catalyzing innovative ideas and approaches that will help us attract and retain the best people in the field,” said Vivek Goel, U of T’s vice-president of research and innovation.

Gordon Keller leads a Medicine by Design project that is working on using stem cells to grow functional liver cells and tissues that will enable researchers to study liver disease and test new drugs more easily. Keller, director of the McEwen Centre for Regenerative Medicine at University Health Network and a professor in U of T’s department of medical biophysics, credits the initiative with bringing together his diverse team, which has expertise in materials chemistry, tissue engineering, 3D bio-printing, liver transplantation and cystic fibrosis therapies.

“The collaborative work we are doing would not have been possible without the strategic vision of Medicine by Design and the transformative investment by the Canada First Research Excellence Fund,” said Keller, Medicine by Design’s associate director of faculty recruitment

Keller has also successfully turned stem cells into different types of heart cells, and is working with CCRM to develop a technology to scale up the production of these heart cells for drug discovery and future use in the clinic.

PhD candidate Ashton Trotman-Grant, centre, discusses his poster with Medicine by Design symposium attendees. Trotman-Grant won the Blueline Therapeutic Translation Award for presenting the poster with the greatest commercialization potential (photo by Neil Ta)

Gary Bader, a professor at U of T’s Donnelly Centre for Cellular and Biomolecular Research, is helming another Medicine by Design team project that is seeking to understand the most complicated computer of all: the human brain. Using the latest technologies for building molecular profiles of individual brain cells, the project will produce millions of data points that Bader’s team of biologists, physicists and mathematicians will use to look for ways to boost the brain’s natural ability to heal after a damage caused by stroke or injury.

Stem Cell

Researchers working on injection-free cell therapy for diabetes

Read about research into therapeutic cell “cloaking”

U of T researchers uncover stem cells' first steps on path to becoming body's organs

Bayer, Versant back commercialization of stem cell therapies in Toronto: "We go where the science is best"

Read more about the historic $114 million grant to Medicine by Design

Medicine by Design symposium at U of T shines spotlight on regenerative medicine

Read about the 20 teams chosen by Medicine by Design

Read more about the historic $114 million grant to Medicine by Design