A recent breakthrough from McEwen Stem Cell Institute has uncovered a key player in pancreatic development: immune cells known as macrophages. These cells were found to play a supportive role in the growth and development of insulin-producing beta-like cells in the pancreas.
The pancreas aids in digestion and releases hormones that regulate blood sugar. However, human pancreas development is highly complex, and little is known about how certain cell populations, including immune cells, contribute to this process. This is crucial because improper immune cell function during pancreatic fetal growth may lead to autoimmune diseases like type 1 diabetes.
While previous evidence suggests that macrophages are important for organ formation, studying this in the human pancreas has been particularly challenging.
In this study, researchers examined the developing pancreas using cutting-edge RNA sequencing techniques. They discovered a variety of hematopoietic (blood forming) cells, including two distinct types of macrophages that appear to be specifically associated with fetal pancreas development.
To explore these findings further, the team created a model using stem cells to grow mini, pancreatic-islet-like structures called organoids. These organoids contained both endocrine (hormone releasing) cells and macrophages, allowing scientists to study their interactions closely.
The results were striking—macrophages helped support the differentiation and survival of the endocrine cells and beta-like cells in particular. Additionally, when the organoids were transplanted into tissue, the presence of macrophages aided the success of the transplant.
These findings suggest that macrophages may be key players in the development of pancreatic endocrine cells, opening new doors for understanding and treating diabetes. By harnessing the power of macrophages, researchers could develop more effective strategies for engineering pancreatic tissue, offering hope for future diabetes therapies.
The first author of this study is Dr. Adriana Migliorini, Scientific Associate at McEwen Stem Cell Institute.
The senior author of this study is Dr. Cristina Nostro, Senior Scientist at McEwen Stem Cell Institute and Associate Professor in the Department of Physiology at the University of Toronto.
This work was supported by the Ontario Institute for Regenerative Medicine, the Howard Webster Foundation, the Canadian Foundation for Innovation and Ontario Research Fund, Breakthrough Type 1 Diabetes International, Canadian Institutes of Health Research, the Banting and Best Diabetes Centre, Canadian Islet Research and Training Network, Medicine by Design, Canada First Research Excellence Fund, and UHN Foundation.
Dr. Adriana Migliorini, Dr. Gordon M. Keller, Dr. Michael H. Atkins, and Dr. Cristina Nostro are co-inventors of one patent application related to this work. Dr. Cristina Nostro also has a patent licensed to Sernova Inc.
Migliorini A, Ge S, Atkins MH, Oakie A, Sambathkumar R, Kent G, Huang H, Sing A, Chua C, Gehring AJ, Keller GM, Notta F, Nostro MC. Embryonic macrophages support endocrine commitment during human pancreatic differentiation. Cell Stem Cell. 2024 Oct 10:S1934-5909(24)00325-4. doi: 10.1016/j.stem.2024.09.011. Epub ahead of print.
Every year, over 650 internationally trained clinical fellows come to UHN to advance their clinical skills and contribute their expertise to Canadian health care. However, starting medical training in a new country is often overwhelming, especially for international clinical fellows who must adjust to different health care systems, cultural norms, and communication styles.
To tackle these challenges, researchers at The Institute for Education Research at UHN developed ‘Transitions’—a specialized program designed to help internationally trained clinical fellows adapt smoothly to medical training in Canada.
The Transitions program offers a flexible blend of online modules with live virtual sessions. It covers critical topics such as navigating the Canadian health care system, effective communication, patient safety, medical ethics, and social determinants of health.
In the pilot program, 65 fellows from 11 different medical specialties participated. They reported improved learning experiences, reduced anxiety, increased confidence and a stronger sense of community with their peers.
“The success of this pilot demonstrates that tailored support can make a meaningful difference,” adds Dr. Ahmed Al-Awamer, lead author of the study and Educational Investigator at The Institute for Education Research at UHN. “This program isn’t just a bridge; it equips internationally trained clinicians with the confidence and connections they need to make an immediate impact in Canadian health care.”
Transitions is not only flexible and practical but also cost-effective, making it a solution that can be easily adopted by other institutions to support medical trainees from around the world. This year, the Transitions program has expanded and accepted around 300 international clinical fellows. The team seeks to continue improving and expanding this program.
Dr. Ahmed Al-Awamer is the lead author of the study and an Educational Investigator at The Institute for Education Research at UHN. Dr. Al-Awamer is also an Associate Professor in the Department of Family and Community Medicine at the University of Toronto (U of T) and a Scholar at The Wilson Centre for Research Education at UHN and U of T.
This work was supported by UHN Foundation, UHN International Centre of Education, and UHN Clinical Education.
Al-Awamer A, Malavade T, Jardine J, Kaya E. 'Transitions': A new pilot programme to support the transitions of new internationally educated clinical fellows. Med Educ. 2024 Nov. doi: 10.1111/medu.15523.
Breast Cancer Awareness Month is an opportunity to highlight both the strides made in research and the ongoing commitment to shape the future of breast cancer treatment and care.
At Princess Margaret Cancer Centre, Senior Scientist and Surgeon, Dr. Michael Reedijk is developing more effective treatments for triple-negative breast cancer (TNBC), a particularly aggressive form of the disease.
Unlike other types of breast cancer, TNBC lacks the receptors that most targeted therapies rely on, making it harder to treat.
“Triple-negative breast cancer accounts for 15-20% of breast cancer cases but has double the mortality rate of the other types, underscoring the tremendous need for targeted therapies.” Says Dr. Reedijk. “There is a great deal of effort going into finding these targeted therapies and that is my lab’s main focus. We aim to uncover drivers and specific characteristics of triple-negative breast cancer.”
One promising avenue of research is immunotherapy, which uses the body's own immune system to attack cancer cells. While this approach has been highly successful in treating some cancers, it has been less effective in TNBC. To improve these outcomes, Dr. Reedijk’s lab is investigating how TNBC interacts with the immune system.
In a recent study, Dr. Reedijk’s lab identified a potential new therapeutic approach that could enhance the treatment efficacy of immunotherapy for TNBC.
TNBC tumours are often heavily infiltrated by immune cells, a unique trait compared to other types of breast cancers. The presence of specific immune cells can impact patient survival: high levels of tumour-associated macrophages (TAMs) are linked to worse outcomes, while increased cytotoxic T cells (CTLs) are associated with better survival. However, the mechanisms that regulate this are poorly understood.
“Immune checkpoint inhibitors—drugs that prevent cancer from evading the immune system—have shown mixed results for TNBC and this is in part because TAMs can block that immune response against cancer cells,” explains Dr. Reedijk. “We are exploring TAMs as a therapeutic target by investigating the molecular mechanisms underlying how they are regulated.”
Dr. Reedijk’s lab previously found that TNBC tumours produce IL1β, a protein that attracts TAMs and reduces CTLs, promoting cancer growth. His team, including first authors Dr. Weiyue Zheng, a Scientific Associate in Dr. Reedjik’s lab and Dr. Wanda Marini, a medical resident at the University of Toronto, sought to investigate this further.
Using pre-clinical models, they found that a protein involved in producing IL1β, called caspase-1, is specifically increased in TNBC and that blocking this protein reduces TAM levels and increases the tumour’s response to immunotherapy.
This study uncovers a key mechanism behind TNCB’s response to immunotherapy and offers a promising target for future treatments. These findings are being explored in patients with TNBC in a phase 1 clinical trial set to open in November, 2024.
To learn more about Dr. Reedijk’s work, see the video below.
This work was supported by the Canadian Cancer Society, the Canadian Institute of Health Research, the Ontario Ministry of Health and Long-Term Care, The Princess Margaret Cancer Foundation and funding from S. Qureshi and family.
Dr. Michael Reedijk is an Associate Professor of Surgery at the University of Toronto.
Zheng W, Marini W, Murakami K, Sotov V, Butler M, Gorrini C, Ohashi PS, Reedijk M. Caspase-1-dependent spatiality in triple-negative breast cancer and response to immunotherapy. Nat Commun. 2024 Oct 1;15(1):8514. doi: 10.1038/s41467-024-52553-6.
A recent study from UHN’s Krembil Brain Institute has revealed important differences in brain activity between Parkinson disease and dystonia, two movement disorders with contrasting symptoms. Parkinson usually causes slow or reduced movement, while dystonia makes muscles contract uncontrollably.
Parkinson and dystonia are both tied to problems in the brain’s movement control systems, specifically in the basal ganglia. These issues involve certain pathways to a specific region called the globus pallidus internus (GPi). In Parkinson, nerve cells in the GPi become more active, while in dystonia, these cells fire less often.
Even though the brain circuits act differently in Parkinson and dystonia, doctors use the same treatment—deep brain stimulation (DBS)—to manage movement symptoms in both conditions. DBS involves placing tiny electrodes in specific parts of the brain to help regulate abnormal brain activity. Still, patients with each disorder respond differently, suggesting disease-specific changes in brain connections.
To investigate this further, researchers studied the brain activity of GPi neurons in patients undergoing DBS treatment. They found that in dystonia, nerve cells fired more slowly, irregularly, and often in bursts, compared to in Parkinson disease. In addition, the researchers discovered that certain brain wave patterns—theta waves in dystonia and low-beta waves in Parkinson—are directly related to the severity of movement symptoms in each condition. This provides single-cell resolution support of earlier studies that found similar connections between these frequency patterns and symptoms in people with Parkinson and dystonia.
The researchers also examined how the brain changes after electrical stimulation, a process called brain plasticity. They found that this process works differently in Parkinson disease and dystonia. In dystonia, the brain seems to be less capable of long-term changes, meaning its wiring is less flexible compared to Parkinson disease.
These findings not only offer a deeper understanding of the differences between Parkinson and dystonia at a cellular level, but can also help to improve treatments like deep brain stimulation by tailoring approaches to each disorder’s specific brain activity patterns and responses to electrical stimulation.
The first authors of this study are Srdjan Sumarac, Doctoral Candidate at Krembil Research Institute, Kiah A. Spencer, Doctoral Candidate, and Dr. Leon A. Steiner, Postdoctoral Researcher at Krembil Research Institute and Universitätsmedizin Berlin.
The senior author of this study is Dr. Luka Milosevic, Scientist at Krembil Research Institute, Affiliate Scientist at KITE Research Institute, and Assistant Professor at the University of Toronto.
This work was supported by Brain Canada in partnership with the Azrieli Foundation, the Banting Research Foundation in partnership with the Dystonia Medical Research Foundation, and UHN Foundation.
Sumarac S, Spencer KA, Steiner LA, Fearon C, Haniff EA, Kühn AA, Hodaie M, Kalia SK, Lozano A, Fasano A, Hutchison WD, Milosevic L. Interrogating basal ganglia circuit function in people with Parkinson's disease and dystonia. Elife. 2024 Aug 27;12:RP90454. doi: 10.7554/eLife.90454.
Canada’s health care system faces significant challenges, with millions experiencing inequities in care and lacking access to essential services. Addressing these challenges requires bold innovation in health care education—empowering health professional students with knowledge and the tools to lead transformative change.
Students have the potential to lead change, but they are often seen as passive learners rather than active participants in change. In a recent article published by Dr. Kathryn Parker, Educational Investigator at The Institute for Education Research, researchers highlight the value of transformative education, which places students at the forefront and teaches them to challenge inequities, question existing systems, and engage in compassionate leadership.
Student-led Learning Environments* (SLEs) are a new way of teaching that offers unique, real-world experiences that bring together students, patients, families, and other health care professionals to create solutions to pressing health care gaps.
Recently, 79 students from 12 different health care professions collaborated in SLEs, dedicating over 8,000 hours to learning, leadership, and service and impacting over 3,000 patients. These programs give students practical, hands-on training and also empower them to help create equitable and compassionate care models. By fostering collaboration, critical thinking, and leadership, SLEs are transforming health care education—and, in turn, health care itself.
This work was supported by UHN Foundation, Employment and Social Development Canada through the Foundation for Advancing Family Medicine, the College of Family Physicians of Canada, and the Canadian Health Workforce Network. Kathryn Parker is an Associate Professor of Transformative Change at the Centre for Advancing Collaborative Healthcare and Education (CACHE) at the University Health Network and the University of Toronto.
Parker K, Binns A, Dupre C, Friesen F, Lising D, Sinclair L, Ng S. "What got you here, won't get you there": Students as leaders of the change we need. Healthc Manage Forum. 2024 Sep. DOI: 10.1177/08404704241259917.
*Recently, SLE’s have been renamed to Student Leadership Experiences. For more information visit the Centre for Advancing Collaborative Healthcare & Education website here.
Did you know that your liver has its own immune cells, ready to defend against infections and keep it healthy? Researchers at McEwen Stem Cell Institute have found a way to create these vital cells—called Kupffer cells (KCs)—from human pluripotent stem cells, opening doors to new treatments for liver disease.
Kupffer cells play a key role in defending the liver against infections and helping to maintain a healthy environment, making the liver more resilient to disease. They are self-renewing, long-lived, and thought to derive from progenitors produced early in fetal life.
Although the characteristics of KCs are well established, the molecular mechanisms that regulate their development and maturation from progenitor cells are poorly understood. It has proven difficult to study this, as replicating the complex liver environment for KC maturation in the lab is challenging and most of the information comes from work in experimental models.
To study this process in humans, scientists first created KC progenitor cells from human stem cells. They then transplanted these progenitors into a specialized experimental model, previously generated by their team, which was modified to provide a suitable environment for KC cell development. They achieved this by replacing the existing liver blood vessel cells in their experimental model—known as liver sinusoidal endothelial cells (LSECs)—with human LSECs generated from human stem cells. This presence of the human LSECs created the perfect environment for KCs to grow.
The team found that these lab-grown human KCs successfully integrated into the liver of pre-clinical models and that the development of the human KCs was dependent on the presence of the human LSECs. Advanced sequencing analysis confirmed that these stem cell-derived KCs had the same unique characteristics as natural KCs. The human KCs were able to perform critical functions characteristic of these cells, specifically phagocytosis, the process of engulfing dead and dying cells.
This research demonstrates the potential to generate human KCs from stem cells, opening new avenues for studying liver disease and developing regenerative treatments.
The first author of this study is Gregory Kent, a doctoral student at McEwen Stem Cell Institute in the lab of Dr. Gordon Keller.
Dr. Gordon Keller, Director of McEwen Stem Cell Institute and Senior Scientist at Princess Margaret Cancer Centre is a co-senior author of the study. Dr. Keller is a Professor in the Department of Medical Biophysics at the University of Toronto.
Dr. Blair Gage, a Scientist at the Ottawa Hospital Research Institute and Assistant Professor at the Department of Cellular and Molecular Medicine at the University of Ottawa, is a co-senior author of the study.
This work was supported by the University of Toronto’s Medicine by Design, the Canadian Institutes of Health Research, and UHN Foundation.
Dr. Gordon Keller is a founding investigator and a paid consultant for BlueRock Therapeutics LP and a paid consultant for VistaGen Therapeutics and Apiary Therapeutics.
Kent GM, Atkins MH, Lung B, Nikitina A, Fernandes IM, Kwan JJ, Andrews TS, MacParland SA, Keller GM, Gage BK. Human liver sinusoidal endothelial cells support the development of functional human pluripotent stem cell-derived Kupffer cells. Cell Rep. 2024 Aug 27;43(8):114629. doi: 10.1016/j.celrep.2024.114629. Epub 2024 Aug 14.
A single blood test is helping doctors catch head and neck cancer relapse up to nearly 15 months earlier than traditional scans and exams. The test was developed by Adela, a biotech company founded on a cell-free DNA technology invented at UHN, based on an exciting breakthrough made by researchers at Princess Margaret Cancer Centre (PM).
The test works by looking for tiny traces of cancer DNA in the blood, which are shed by cancer cells and are detectable even before symptoms appear. "Most recurrences are caught after the patient notices symptoms, but this test can find the cancer much sooner," says Dr. Geoffrey Liu, a Senior Scientist at PM.
In a study involving more than 300 patients, and recently published in The Annals of Oncology, significant differences in recurrence-free survival (RFS) were observed. These patients had been treated for different stages of head and neck cancer, including cancers caused by human papillomavirus (HPV).
The technology behind this test was developed from research co-led by PM Senior Scientists Dr. Daniel De Carvalho, Dr. Scott Bratman, and their teams, who discovered that specific DNA changes in cancer cells could be detected in the blood. This finding paved the way for a more affordable and effective way to monitor cancer.
Adela is now refining this blood test, hoping it can be used to monitor other types of cancer. "This test has huge potential to help us catch cancer early and improve treatment for patients," says Dr. De Carvalho.
Dr. Geoffrey Liu is a Senior Scientist and the Director of Applied Molecular Profiling Pharmacogenomic Epidemiologic Laboratory at Princess Margaret Cancer Centre. He is also a Professor at the Departments of Medicine and Epidemiology at the University of Toronto.
Dr. Daniel De Carvalho is a Senior Scientist at Princess Margaret Cancer Centre and a Tier 2 Canada Research Chair in Neoplasms. Dr. De Carvalho is also a Professor at the Department of Medical Biophysics, University of Toronto and the Chief Scientific Officer of Adela, Inc.
Dr. Scott Bratman is Senior Scientist at Princess Margaret Cancer Centre Research Institute and Associate Professor of Radiation Oncology and Medical Biophysics at the University of Toronto.
This work was supported by the Adela, Inc., the Princess Margaret Cancer Centre Head and Neck Translational Program, and The Princess Margaret Cancer Foundation.
Detailed disclosures regarding conflicts of interest are provided within the publication.
G. Liu, S. Huang, L. Ailles, K. Rey-McIntyre, C. Melton, S. Shen, J. Burgener, B. Brown, J. Zhang, J. Min, Y. Wang, O. Hall, J.T. Jones, K. Budhraja, J. Provance, E. Sosa, A. Licon, A. Williams, S. Bratman, B. Allen, J. Zhang, A.-R. Hartman, D. De Carvalho. Clinical validation of a tissue-agnostic genome-wide methylome enrichment MRD assay for head and neck malignancies. Annals of Onc. 2024 Sep, 14: 0923-7534. Doi: https://doi.org/10.1016/j.annonc.2024.08.2348.
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