Drs. Alexander Mikryukov and Gordon Keller at McEwen Stem Cell Institute recently discovered how to produce endocardial cells—a type of cell that lines the interior of the heart—from stem cells in the laboratory.
The stem cells that they used are known as human pluripotent stem cells. These cells are capable of giving rise to all of the different cell types found in the human body. Devising ways to coax these stem cells to produce specific types of cells is an area of ongoing research.
“Endocardial cells are formed during one of the earliest stages of heart development and function to stimulate the formation of the first muscle tissue in the heart,” explains Dr. Mikryukov, the lead author of the study. “They also produce cells that are part of the blood vessels and the valves of the heart.”
The human body is made up of roughly 37 trillion cells; all of them originate from a single cell—the fertilized egg. The path of growth from one cell to 37 trillion is highly complex—everything must happen at the right time and in the right place.
In the body, cells use chemical signals to guide the development of new cells so that they have the characteristics needed to perform their role. To identify which chemicals are responsible for giving rise to endocardial cells, the team recreated conditions for early heart development using pluripotent stem cells as an experimental model. They also used advanced gene sequencing approaches that are capable of providing a snapshot of the genes expressed in each individual cell.
These analyses revealed that the protein BMP10 plays a key role in regulating the development of endocardial cells in early heart development. They also showed that the lab-derived endocardial cells had very similar characteristics to embryonic endocardial cells.
“Our results highlight the power of using stem cells as a model to identify the mechanisms behind the formation of the heart tissues during embryonic development,” says Dr. Keller, senior author of the study.
The ability to produce endocardial cells in the laboratory opens new avenues to modelling heart development and disease—and could help to accelerate the development of treatments for heart conditions such as valve diseases.
This work was supported by the Canadian Institutes of Health Research and the Toronto General & Western Hospital Foundation. G Keller holds a Tier 1 Canada Research Chair in Embryonic Stem Cell Biology.
Mikryukov AA, Mazine A, Wei B, Yang D, Miao Y, Gu M, Keller GM. BMP10 Signaling Promotes the Development of Endocardial Cells from Human Pluripotent Stem Cell-Derived Cardiovascular Progenitors. Cell Stem Cell. 2020 Oct 27. doi: 10.1016/j.stem.2020.10.003.
Welcome to the latest issue of The Krembil.
The Krembil is the official newsletter of the Krembil Research Institute (formerly the Toronto Western Research Institute). Research at Krembil is focused on finding innovative treatments and cures for chronic debilitating disorders, including arthritis and diseases of the brain and eyes.
Stories in this month’s issue include:
• Unifying Research, Education & Care: Generous $25 million donation enables creation of the Schroeder Arthritis Institute.
• Immunologist Joins the Krembil Team: New scientist, Dr. Olga Lucia Rojas, studies the link between the gut and neuroinflammation.
• Having it Both Ways: Krembil researchers validate new, highly specific & sensitive criteria for classifying lupus.
• A Case for Research: Study proposes research roadmap to improve knowledge of spontaneous hydrocephalus in adults.
• Well in Hand: Study explores how the brain restores hand function after a hand transplant.
• The Importance of Being Open: Study implicates syntaxin as a gatekeeper of information in the brain and spinal cord.
Dr. Daniel De Carvalho’s laboratory at Princess Margaret Cancer Centre has commenced a collaborative drug discovery research program with Pfizer’s Center for Therapeutic Innovation (CTI). The collaboration will leverage Dr. De Carvalho’s expertise in immunotherapy and aims to screen, identify and optimize potential drug candidates that trigger the body’s own immune system to kill cancer cells.
This research collaboration will match Pfizer’s drug discovery expertise with novel mechanisms of disarming cancer cells against the body’s own immune response by mimicking a viral infection to the cancer cells, which was previously identified by a team of researchers led by Dr. De Carvalho.
“Our prior work provides an exciting foundation for drug development efforts and could lead to the development of a completely new class of drugs that are able to exploit the body’s own genome against cancer,” says Dr. De Carvalho.
UHN’s Technology Development and Commercialization office helped facilitate the collaboration.
“We are thrilled to enter into this new collaboration with Pfizer,” says Mark Taylor, Director, Technology Development and Commercialization at UHN. “This new relationship pairs Dr. De Carvalho’ s deep know-how with Pfizer’s drug-discovery engine, to accelerate the possibility of a new treatment to patients, sooner,” he said. “Our collaboration with Pfizer illustrates our commitment to research partnerships that allow access to the latest technology to enrich possibilities for patients world-wide.”
The brain is bathed in a protective fluid called cerebrospinal fluid. In a condition known as hydrocephalus, the fluid fails to drain properly from cavities in the brain called ventricles and puts pressure on the surrounding tissue.
The type of hydrocephalus that is most commonly seen in adults—normal pressure hydrocephalus—can be caused by an infection, tumour or head trauma. However, the condition is often deemed idiopathic, which means that the cause of the fluid accumulation is unknown.
To shed light on this elusive form of hydrocephalus, a research team led by Krembil Clinical Investigator Dr. Alfonso Fasano highlighted the current knowledge gaps in diagnosis and treatment, and proposed a research roadmap to address them.
“There are currently no standardized diagnostic criteria for normal pressure hydrocephalus and it often goes misdiagnosed because the symptoms can be similar to neurodegenerative conditions such as Parkinson disease,” explains Dr. Fasano. “We must take a research-oriented approach to defining diagnostic guidelines and understanding treatment outcomes.”
The researchers highlighted the actions needed to advance our understanding of the condition, which are listed below:
● Develop unified international diagnostic criteria
● Conduct population-based studies to reveal how the disease develops and progresses in a variety of individuals
● Build international biobanks where samples from diverse patient populations can be stored and shared
The roadmap also emphasizes the need for better ways to assess how normal pressure hydrocephalus is treated. Currently, the condition is treated through shunting—a procedure in which a small tube is inserted into the brain to drain excess fluid. A key problem is that the test used to decide whether shunting should be used is unreliable. To address this, the roadmap calls for rigorous clinical trials (ie, randomized controlled trials) that involve a variety of different patients. These trials will help to reveal more effective ways to decide which patients should receive the procedure.
“In order to better treat those affected by this disorder, we need a stronger understanding of the underlying factors,” says Dr. Fasano. “A unified approach is the best way forward. By working together, the research community is uncovering the molecular and biological mechanisms at play so we can improve the quality of life for patients living with this condition.”
Fasano A, Espay AJ, Tang-Wai DF, Wikkelsö C, Krauss JK. Gaps, Controversies, and Proposed Roadmap for Research in Normal Pressure Hydrocephalus [published online ahead of print, 2020 Sep 22]. Mov Disord. 2020;10.1002/mds.28251. doi:10.1002/mds.28251
Researchers at the Krembil Research Institute have revealed that a protein—known as syntaxin—could hold the key for new therapies for a variety of neurological disorders.
Syntaxin plays a key role in how neurons—specialized cells in the brain and nervous system—transmit information throughout the body. Neurons communicate with other cells at narrow gaps known as synapses, where neurotransmitters are released. These neurotransmitters serve to ‘bridge the gap’ between the cells by passing on the signal.
The release of neurotransmitters is key to the process known as synaptic transmission, which enables the flow of electrical information between the brain, spinal cord and body.
At the molecular level, syntaxin serves as a switch and changes shape from a ‘closed’ to an ‘open’ state. Once in the ‘open’ state, syntaxin acts in concert with other proteins to enable the release of the neurotransmitters. When syntaxin or other proteins involved in this process are defective, certain neurological disorders can arise.
“Using an experimental model, we introduced a version of syntaxin that was locked in the ‘open’ state. This version of syntaxin was able to overcome losses in proteins that are implicated in a wide spectrum of childhood epilepsy and autism spectrum disorders,” says Dr. Sugita.
These findings position syntaxin as a key player in synaptic transmission, and suggest that drugs, and other small molecules, could be developed to push syntaxin to the ‘open’ state as part of a strategy to treat certain neurological diseases.
This work was supported by the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research, The Welch Foundation, National Natural Science Foundation of China, the United States National Institute of Neurological Disorders and Stroke, the Dengfeng Initiative of the Global Talents Recruitment Program, and the Toronto General & Western Hospital Foundation.
Tien CW, Yu B, Huang M, Stepien KP, Sugita K, Xie X, Han L, Monnier PP, Zhen M, Rizo J, Gao S, Sugita S. Open syntaxin overcomes exocytosis defects of diverse mutants in C. elegans. Nat Commun. 2020 Nov 2;11(1):5516. doi: 10.1038/s41467-020-19178-x.
Clinical researchers rely on robust selection criteria when identifying patient groups for their research studies. In recent years, Dr. Sindhu Johnson, a Clinician Scientist at Krembil Research Institute, has been jointly leading a global collaboration to develop new, more effective criteria to identify individuals with lupus (also known as systemic lupus erythematosus).
Lupus is an autoimmune disease in which the immune system attacks the body’s healthy tissues and organs, causing pain and damage. “The disease can develop and present itself in many ways,” says Dr. Johnson. “This makes it difficult to grasp and define.”
In 2019, Dr. Johnson’s team, which spanned continents and included fellow Krembil researchers Drs. Dafna Gladman, Jorge Sanchez-Guerrero, Murray Urowitz and Zahi Touma, published their new criteria. The researchers carefully weighed results from lab tests for antibodies and proteins along with other clinical factors, such as the occurrence of fevers or seizures, to devise their classification system.
While the new criteria were proven successful for a general population, the research community still needed to know how they fared for specific patient groups. For instance, would the criteria work equally well for males and females?
Dr. Johnson’s team then sought to validate the criteria against sex, ethnicity and disease stage and have now published their results.
The team evaluated the new criteria for sensitivity—correctly identifying patients with lupus—and specificity—correctly identifying patients without lupus. The criteria performed exceptionally well across all patient groups, with both quantities ranging from 89 to 100%.
This combination of excellent sensitivity and specificity is a leap forward because previous criteria have been only top-performing in one measure. For instance, criteria published in 2012 by the Systemic Lupus International Collaborating Clinics Group offered a sensitivity of 83% and a specificity of 93% for women, whereas Dr. Johnson’s criteria achieved 97% and 94%.
A key finding from the validation study was that the criteria were robust for patients with early disease. This will enable the more timely inclusion of patients in clinical trials and observational studies.
This work was supported by the European League Against Rheumatism; the American College of Rheumatology; the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health; and Toronto General & Western Hospital Foundation.
Johnson SR, Brinks R, Costenbader KH, Daikh D, Mosca M, Ramsey-Goldman R, Smolen JS, Wofsy D, Boumpas DT, Kamen DL, Jayne D, Cervera R, Costedoat-Chalumeau N, Diamond B, Gladman DD, Hahn B, Hiepe F, Jacobsen S, Khanna D, Lerstrøm K, Massarotti E, McCune J, Ruiz-Irastorza G, Sanchez-Guerrero J, Schneider M, Urowitz M, Bertsias G, Hoyer BF, Leuchten N, Tani C, Tedeschi SK, Touma Z, Schmajuk G, Anic B, Assan F, Chan TM, Clarke AE, Crow MK, Czirják L, Doria A, Graninger WB, Halda-Kiss B, Hasni S, Izmirly PM, Jung M, Kumánovics G, Mariette X, Padjen I, Pego-Reigosa JM, Romero-Diaz J, Rúa-Figueroa Í, Seror R, Stummvoll GH, Tanaka Y, Tektonidou MG, Vasconcelos C, Vital EM, Wallace DJ, Yavuz S, Meroni PL, Fritzler MJ, Naden R, Dörner T, Aringer M. Performance of the 2019 EULAR/ACR classification criteria for systemic lupus erythematosus in early disease, across sexes and ethnicities. Ann Rheum Dis. 2020 Oct. doi: 10.1136/annrheumdis-2020-217162.
The international award recognizes research teams that have made significant contributions to advancing the field of cancer immunotherapy. The field is thriving, with a wide range of anticancer therapies in development—and teamwork has been crucial to build this burgeoning field.
Dr. Mak and Ohashi began working together 36 years ago in 1984, just after Dr. Mak made his fundamental discovery of the T cell receptor (TCR). Their work has revealed many of the underlying concepts of cancer immunotherapy—including the affinity/avidity model of thymocyte selection, identifying T cell ignorance as a way to avoid autoimmunity, and showing conditions under which these T cells can be activated to promote immune surveillance in the presence of a tumor.
Much of the focus of their work has been to take basic biology insights and apply them to improving the immune response to tumors. For example, they revealed the importance of interleukin 7 and tumor necrosis factor-alpha in promoting anti-tumor immunity, both of which are being tested in various clinical trials for cancer and infectious diseases.
In 2005, Pam Ohashi, with help from Linh Nguyen, laid the groundwork for establishing the Tumor Immunotherapy Program at the Princess Margaret Cancer Centre. The centre then recruited Naoto Hirano and Marcus Butler, who initiated clinical trials in therapies involving tumor-infiltrating lymphocytes and TCR transduced T cells. Lillian Siu joined the team in 2015 and began serving as co-lead of the Tumor Immunotherapy Program. Over the past five years the program has run 30 investigator-initiated and industry-sponsored trials and set up a comprehensive immune profiling team led by Ben Wang. In 2015, David Brooks and Tracy McGaha also joined the team. These individuals represent a selection of the 37 team members recognized by the award.
In the over 35 years since SITC was established, 17 teams have received this recognition. Teams that have been honoured in the past include those led by Dr. Thierry Boon, who was the first the molecularly characterize a human antigen recognized by patients’ T lymphocytes, and Dr. Steven A. Rosenberg, who played a pioneering role in the development of T cell therapies for patients with cancer.
To see a video of the virtual award ceremony, click here.
Congratulations to the entire team!
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