Team Projects – Cycle 1 (2016-2019)

Lead Investigator:

John Dick
Princess Margaret Cancer Centre, University Health Network
Department of Molecular Genetics, University of Toronto

Co-Investigators:

Norman Iscove, Mathieu Lupien, Gary Bader, Quaid Morris, Igor Jurisica, Shana Kelley

Project Description: Worldwide, 50,000 hematopoietic stem cell transplant (HSCT) procedures are undertaken annually to replace a person’s blood-forming cells — hematopoietic stem cells (HSCs) — to treat blood disorders and cancers, yet two-thirds of patients who need HSCT lack matched donor tissue. If more donors where available and the efficacy and safety of HSCT improved, HSCT could benefit more patients with blood diseases. Cord blood (CB) biobanking is being developed worldwide to increase the probability of finding matched donor HSC. However, HSC number in CB is usually limiting and methods for large-scale expansion remain to be developed. In addition to limiting HSC numbers, HSCT is inefficient, as many HSC do not get to the relevant areas in the body and/or die following transplantation. This project will generate methods to increase HSC number and/or overcome transplant inefficiencies from adult and CB sources. It will combine functional data with bioinformatics analyses to identify regulators of stemness and HSC survival pathways and then use this information to develop therapeutic targets for preclinical testing. It will also prioritize up to five candidates for the translational pipeline, with one candidate ready to move forward. With the Centre for Commercialization of Regenerative Medicine (CCRM), this project will test top candidates for batch-fed pre-clinical HSC expansion. With CCRM and UHN Technology Development and Commercialization assistance, potential licensees for this innovation have been identified and the formation of a company will be explored. The model selected will depend on the patent portfolio developed at study completion.

Lead Investigator:

Jason Moffat
Department of Molecular Genetics, University of Toronto

Co-Investigators:

Gordon Keller, Brenda Andrews, Charlie Boone, Stephane Angers

Project Description: Source material for hematopoietic (bone marrow) transplantation is in great demand as at least 20,000 allogeneic transplants are performed each year. Despite advances in using umbilical cord blood, donor material remains restricted by limited stem cells and the lack of ethnic diversity to provide sufficiently matched material. Thus, alternative sources of patient-specific hematopoietic stem cells (HSCs) are required. The generation of HSCs has been a long-standing goal of stem cell biologists working in the field of developmental hematopoiesis. Despite extensive efforts in this area over the past two decades, it is not yet possible to derive HSCs in vitro. This failure is largely due to a lack of fundamental insights into genes and pathways that control HSC development. This team, which brings together expertise in stem cell biology, cell biology, developmental signalling pathways, and genetic screens, aims at improving methods to achieve generation of HSC. The group plans to identify better markers to track and purify key cell intermediates as well as uncover key genes/pathways that lead to HSC development. The ultimate goal is to establish a robust platform that can be used to identify and validate novel genetic factors and protein tools to improve understanding of the process that will lead to our ability to re-constitute the entire blood ontogeny in a patient-specific manner. The methods proposed are cutting-edge and no other team in the world has this combination of technologies, approaches and expertise to make advances in hematopoietic cell therapies.

Return to top of page

Lead Investigator:

Gary Bader
Donnelly Centre for Cellular and Biomolecular Research and Department of Molecular Genetics and Department of Computer Science, University of Toronto

Co-Investigators:

Freda Miller, David Kaplan, Derek van der Kooy, Michael Moran, Aaron Wheeler, Cindi Morshead, Quaid Morris, Michael Hoffman, Lincoln Stein, Sidhartha Goyal, Trevor Pugh, Michael Wilson

Project Description: The brain is built from many different types of cells and their interconnections, forming an amazingly complex “computer” that controls all aspects of our lives. Better understanding the development of this complex system will lead to improved treatments of nervous system injuries, such as stroke, and neurodevelopmental disorders, such as cerebral palsy. These treatments will have important benefits to Canada, and internationally, in terms of improved quality of life for patients and reduced health-care costs for society. All cells in the brain originate from stem cells, which also maintain and repair brain tissue in adulthood. This project proposes a transformative approach to discovering the circuits that control brain tissue growth that will provide new insights into normal and pathological development and aging, help develop drugs that activate stem cells for tissue repair, and enable the growth of pure populations of specific cell types potentially useful for replacing damaged tissue. This project will measure millions of data points about gene expression in these cells and computationally mine this data to identify cell states, state transitions and critical points that will be targeted with the aim of controlling stem cell fate for therapeutic use.

Lead Investigator:

Shana Kelley
Department of Pharmaceutical Sciences, Department of Biochemistry, Department of Chemistry and Institute of Biomaterials & Bioengineering, University of Toronto

Co-Investigators:

Keith Pardee, John Dick

Project Description: Efficient expansion and differentiation of stem cell cultures remains a bottleneck in the use of stem cells and their differentiated products in regenerative medicine. This project proposes to overcome this bottleneck by developing systems for real-time monitoring of cultures. To achieve this goal, a unique team of early- and mid-career researchers has been assembled with expertise in the development of ultrasensitive multi-analyte chip-based sensors, stem cell biology, microfluidic systems for highly specific cell separations, gene networks and synthetic biology. As part of this seed grant, the team will develop robust electrochemical sensor technology for a panel of analytes using cell-free systems to allow for versatile and high-capacity culture monitoring. Future advances aim to engineer control systems to integrate dynamic ultrasensitive sensors into control loop algorithms to exert spatial and temporal control of cell and tissue developmental and morphogenetic response. The devices that will be generated will enable large-scale stem cell cultures to be monitored and will create individual technologies of significant value for advanced regenerative medicine therapies. The versatile innovations developed in this project will have commercial potential both in the regenerative medicine sector as well as in the life sciences tools and clinical diagnostics markets.

Lead Investigator:

Andras Nagy
Lunenfeld-Tanenbaum Research Institute, Sinai Health System
Department of Obstetrics and Gynaecology and Institute of Medical Science, University of Toronto

Co-Investigators:

Martin Post, Tom Waddell

Project Description: The transplantation of pluripotent stem cell (PSC)-derived therapeutic cells to treat disease is challenged by the risk of introducing malignant cell types to the patient. Cell transplants leading to uncontrolled growth can arise due to genetic mutations that arise from in vitro expansion of PSCs. The Nagy lab has pioneered the generation of mouse and human PSCs carrying a “fail-safe” genetic system that enables selective ablation of “ill-behaving,” highly proliferating cells post-transplantation. The Nagy lab will further extend the “fail-safe” system by identifying novel genes whose function is critically important for cell division. The goal is to use genes that, when knocked out or turned off, lock cells into a quiescent state. Controlling the expression of such genes will allow the progression or stalling of the dividing cells with the ON/OFF administration of a small drug. The Post and Waddell labs will lead the generation of fail-safe therapeutic cells and their testing after transplantation into a model organism/disease, respectively. The Team will test the ability of “fail-safe” blood and lung cells to 1) respond to our engineered stop switch in vitro and in vivo and 2) ameliorate pathologies in our animal models of lung diseases, which include cystic fibrosis and chronic obstructive pulmonary disease. The use of “fail-safe” cells in preclinical studies will accelerate the development of safe cell clinical therapies in human that will bring Canada into a leading role for stem cell therapies and ultimately help patients suffering from debilitating degenerative disease.

Lead Investigator:

Ulrich Tepass
Department of Cell and Systems Biology, University of Toronto

Co-Investigators:

Helen McNeill, Anne-Claude Gingras, Rodrigo Fernandez-Gonzalez, Juri Reimand, Christopher Yip

Project Description: Effective strategies in tissue and organ regeneration would improve the treatment options for a large number of pathologies that compromise organ function. This is particularly true for aging populations in which failure of organs, such as the heart, the retina, the kidney, the lung or the liver, will occur with greater frequency. Re-establishing functional tissues and organs from stem cells or small populations of progenitor cells requires the carefully controlled process to establish tissues of the correct size while preventing tumour formation. At the same time, cells must undergo differentiation to attain normal tissue structure and function. The most common type of tissue is the epithelium, a sheet-like tissue of tightly adherent polarized cells that forms a crucial component of virtually all organs in the human body. It is important to understand how the mechanisms that regulate tissue growth interplay with the cellular machinery that controls the anatomical and physiological features of epithelial tissues to regenerate a stable, functional tissue of normal size. We lack a comprehensive understanding of the molecular networks that couples epithelial cell architecture to cellular signaling that regulates tissue and organ growth during regenerative processes. Our team will elucidate the molecular basis of tissue regeneration using a set of complementary approaches at the leading edge of biomedical research. Understanding this network is a key prerequisite for developing rational strategies to control and manipulate tissue regeneration in a therapeutic context.

Return to top of page

Lead Investigator:

Michael Laflamme
Toronto General Research Institute, University Health Network
Department of Laboratory Medicine and Pathobiology, University of Toronto

Co-Investigators:

Gordon Keller, Hai-Ling Margaret Cheng, Andras Nagy

Project Description: Heart disease remains the leading cause of death in Canada and worldwide. After a heart attack (also known as myocardial infarction, or an MI), the heart muscle lost is replaced by non-contractile scar tissue, often initiating progressive heart failure. Current options for treating post-MI heart failure are limited, and this remains a disease with high morbidity, mortality and societal costs. The ability to “remuscularize” the injured heart by transplanting cardiomyocytes (heart muscle cells) derived from human embryonic stem cells (hESCs) represents a potentially revolutionary new therapy for patients suffering from this disease. In past work, this team has developed efficient methods for generating large quantities of human embryonic stem cell-derived cardiomyocytes (hESC-CMs), and shown that the transplantation of these cells mediates beneficial effects on contractile function in models of post-MI heart failure. This project is aimed at overcoming critical remaining barriers to the successful development of hESC-based cardiac therapies. First, the team will develop improved populations of hESC-CMs that have the appropriate functional properties for cardiac repair. Second, to address important safety concerns, it will engineer hESC-CMs to reduce the risk of both graft cell-related arrhythmias and tumour formation. Third, it will develop novel imaging methods to non-invasively track the size and location of hESC-CM graft cells in vivo. The successful completion of this work will bring closer the goal of a Canada-based, first-in-humans clinical trial with hESC-CMs in post-MI heart failure.

Return to top of page

Lead Investigator:

David McMillen
Department of Chemical and Physical Sciences, University of Toronto Mississauga

Co-Investigators:

Keith Pardee, Radhakrishnan Mahadevan, Dana Philpott, Tae-Hee Kim, John Parkinson

Project Description: Inflammatory bowel diseases (IBDs) affect 1 in 200 people in Ontario, and while various factors have been identified, the ultimate cause of these diseases is currently unknown. One major contributor has been identified, however: a defect in a particular protein that affects the gut lining’s ability to renew itself properly. This protein is stimulated by molecules that come from the bacteria living in the intestines (the “gut microbiome”), and the details of that connection have only recently been discovered (by a member of our team). The plan for this project is to create a new probiotic bacterium that can sense the level of these molecules and produce more of them when needed, providing extra stimulation to the cells in the gut lining and helping improve or cure the disease for people whose protein detectors need more of the stimulatory molecule in order to respond properly. This team combines expertise in synthetic biology, biological engineering, gut stem cell research, and advanced genetic analysis to address the challenges of designing this brand-new approach to IBD therapy. The gut microbiome is emerging as a key player in a wide range of human health issues, including bowel diseases but extending to metabolic, immunological and even neural diseases. The overall goal is to establish ways of systematically sensing and manipulating the environment inside the intestine, laying the groundwork for a wide range of bacteria-mediated therapies that improve human health by the repairing the conditions in the intestine.

Lead Investigator:

Jeff Wrana
Lunenfeld-Tanenbaum Research Institute, Sinai Health System
Department of Molecular Genetics, University of Toronto

Co-Investigators:

Laurence Pelletier, Christopher Yip, Sevan Hopyan, Anna Goldenberg, John Parkinson, Liliana Attisano, Daniel Schramek, Luca Scardovi, Daniel Durocher

Project Description: Research on organ development, their response to injury and their regenerative capacity has historically been studied whole tissue or groups of cells. However, organs require millions of individual cells to act as a collective that is responsible for the unique functions of each organ. Studies at the tissue level provide an exquisite understanding of how organs function, but we know almost nothing about how the activity of individual cells is corralled to support the overall structure and function of organs. Understanding individual cell behaviour is also critical to understanding how regeneration of functional tissue could be stimulated. For example, when the intestinal lining is damaged, individual stem cells get tasked with the job of repairing the tissue. The research in this proposal focuses on illuminating how individual cells are instructed to drive tissue repair. This multidisciplinary team is developing and applying new imaging technologies, gene editing strategies and next-generation sequencing to map individual cell behaviour in a tissue and will be linked to mathematical models that predict how perturbing individual cells might ultimately affect organ function. These discoveries can then be applied to the development of new drugs for the regenerative medicine clinic, for example, by making the growth of human replacement tissues more efficient, or by illuminating how to get replacement tissue to functionally integrate into the recipient organ. This research will also enable the design of therapies aimed at awakening dormant regenerative programs in damaged organs, thereby stimulating our own tissue to repair itself.

Return to top of page

Lead Investigator:

Jason Fish
Department of Laboratory Medicine and Pathobiology, University of Toronto

Co-Investigators:

Michael Wilson, Michael Hoffman, Jennifer Mitchell, Markus Selzner

Project Description: Liver transplantation is the only chance of a cure for patients with end-stage liver disease or advanced liver cancer; however, due to a shortage of donor organs, 30 per cent of patients will die or are delisted due to disease progression before an organ becomes available. Some available donor livers, particularly after prolonged cold storage or those from older donors, are not suitable for transplantation due to liver sinusoidal endothelial cell (LSEC) death. The team’s objective is to increase the number of organs available for transplant by developing novel ways to produce patient-specific LSECs for regenerative liver therapy. Strategies to produce and engraft patient-specific LSECs will improve transplant outcomes, especially when donor livers are not in pristine condition. To achieve these objectives, the team will determine the distinct gene expression signature of LSECs, identify the role of the liver microenvironment in maintaining this signature, and express LSEC regulators to produce functional human LSECs from patient stem cells. Innovations will be tested in pre-clinical animal models followed by clinical trials. This project is unique globally as the team is focusing on human LSECs whereas most studies are conducted on mouse or rat cells. The team is able to achieve its objectives through collaboration between fundamental and clinical scientists, providing access to healthy human liver biopsies and the expertise to conduct the proposed cellular engineering. Canadian researchers are leaders in stem cell medicine; this project builds on that foundation to benefit Canadians through advances in regenerative medicine that will improve the health of patients with liver disease.

Lead Investigator:

Gordon Keller
McEwen Centre for Regenerative Medicine and Princess Margaret Cancer Centre, University Health Network
Department of Medical Biophysics, University of Toronto

Co-Investigators:

Ian McGilvray, Molly Shoichet, Axel Guenther, Christine Bear

Projects Description: The goal of this project is to generate functional liver cells and engineered liver tissues from human pluripotent stem cells (hPSCs) to 1) study human liver disease, 2) test new therapeutic approaches to treat liver disease, and 3) assess new drugs in a predictable and reproducible manner. To achieve this goal, five principal investigators with complementary expertise have been brought together. The Keller lab, leaders in stem cell biology, will derive the complete spectrum of cell types found in the human liver from hPSCs. The McGilvray lab has access to high quality primary human tissue from livers used for transplantation at the Toronto General Hospital. They will isolate and characterize primary liver cell populations, compare them to hPSC-derived cells, and use this information to predict which cells are best for transplant. The Shoichet lab, with their expertise in materials chemistry and tissue engineering, will use these cells to engineer 3D tissues in hydrogels that have been designed to mimic critical aspects of the liver environment. As a complementary engineering approach, the Guenther lab will use these cells to 3D print tissue constructs designed to imitate the liver bile ducts. These ducts can be used to recapitulate cystic fibrosis (CF), allowing the Bear lab to test emerging CF therapies. Finally, these engineered cells and tissues will be evaluated for their ability to rescue liver failure in mice. Collectively, this project aims to determine the most effective new therapies to treat Canadians with liver disease.

Return to top of page

Lead Investigator:

Shaf Keshavjee
Toronto General Research Institute, University Health Network
Division of Thoracic Surgery and Institute of Biomaterials & Bioengineering, University of Toronto

Co-Investigators:

Mingyao Liu, Marcelo Cypel

Project Description: University Health Network and the University of Toronto have enjoyed a proud history of world firsts in the field of organ transplantation. Breakthroughs include the first successful single and double lung transplant surgeries, and lead investigator Dr. Shaf Keshavjee’s advancement of the Toronto Ex Vivo Lung Perfusion (EVLP) system. While each of these medical feats has greatly benefited patients worldwide, the current gap in integrating technological innovations, combined with a growing critically ill patient population, suggest much more can be done to address end-stage organ failure at the patient bedside. This research team will embark on a new research initiative that will focus on enhanced organ assessment and novel organ repair therapies. This includes the development of advanced EVLP systems that will enable comprehensive repair and regeneration and truly transform the transplant field, and the testing of safe treatment methods that can be implemented worldwide. The drive to create healthier organs for transplant will result in:

• reduced wait times for patients on transplant wait lists;
• increased quality of life for those that receive transplants; and
• drastically reduced direct and indirect health-care costs related to the care of pre- and post-transplant patients worldwide.

The research team will aim to improve critical transplant patient care and strengthen Canada’s case for being “World First” in organ transplantation.

Lead Investigator:

Tom Waddell
Toronto General Research Institute, University Health Network
Division of Thoracic Surgery & Institute of Biomaterials & Bioengineering, University of Toronto

Co-Investigators:

Cristina Amon, Aimy Bazylak, Hai-Ling Margaret Cheng

Project Description: Lung disease is an important clinical problem and for patients with end-stage lung disease, transplantation has become both a cost-effective treatment approach and often the only life-saving option. Ideally we need access to “off-the-shelf” replacement grafts reducing the dependency on donor organs, wait times and risk of death. In the lung, organ regeneration is achieved by using biohybrid devices with partially synthetic or natural scaffolds. The approach is to repopulate with new cells, scaffolds in which the resident cells have been removed, and use for functional replacement of damaged tissue. While transplantation of regenerated whole lungs is a far-off goal, we exploit the simpler system of the trachea with which we have extensive expertise while addressing key issues that will set the foundation for future clinical application of whole lung grafts. At the end of the funding period, this team expects to begin clinical translation of a functional tracheal biograft used to address small airway and larger tracheal defects, respectively. The optimized lung and trachea bioreactors developed during the project can result in commercial products via licensing to already existing lung biotech companies or through company creation ventures with focus on enhanced organ-specific bioreactors. In parallel, this team proposes to expand imaging approaches and develop groundbreaking methods allowing for non-invasive assessment of transplanted grafts, a significant and necessary step towards clinical translation. Completion of this work will set in motion a therapeutic strategy with the potential to save lives and vastly improve the quality of life of Canadians suffering from end-stage lung disease.

Return to top of page

Lead Investigator:

Michael Sefton
Department of Chemical Engineering and Applied Chemistry, University of Toronto

Co-Investigators:

Penney Gilbert, Alison McGuigan, Clint Robbins, Philip Marsden, Christoph Licht

Project Description: Skeletal muscle loss caused by surgery, trauma or increased pressure within a limb (compartment syndrome) results in loss in function. As an alternative to tissue grafting, which is limited by graft availability and immunological issues, we propose to use a synthetic, regeneration-inducing biomaterial scaffold (without cells) to “prepare the ground” for endogenous repair by the resident stem cells, known as satellite cells (SC). In order to mobilize and direct SC-mediated endogenous repair with purpose-built biomaterials (“biomaterials by design”), this project will build a comprehensive view of SC interactions with their surroundings (the “niche”) and how the niche, modulated by custom designed biomaterials, affects, if not also controls, the life cycle of SC and their progeny. It will focus on the intimate relationship between the muscles, the blood vessels and the innate inflammatory response that provide instructive cues to guide tissue regeneration. Poor revascularization and acute inflammation are features of critical-sized tissue defects from traumatic insult. This team will aim to convert this degenerative niche into a regenerative niche, primarily with a new suite of biomaterials, such as one that promotes vascularization or one that targets a particular cell pathway to activate and restore the endogenous repair process in situ for a wide range of muscle conditions. Designing biomaterials to modify specific aspects of the muscle “niche” to support and synergize with innate repair mechanisms will be a unique and effective off-the-shelf regenerative medicine solution. This collaborative effort will address a global unmet clinical need to restore tissue integrity and strength following skeletal muscle trauma.

Return to top of page

Lead Investigator:

James Ellis
Developmental & Stem Cell Biology, Hospital for Sick Children
Department of Molecular Genetics, University of Toronto

Co-Investigators:

Ben Blencowe, John Calarco, Freda Miller, Quaid Morris

Project Description: This project will discover RNA binding proteins (RBPs) that promote stem cell expansion and neuron specification. The team comprises University of Toronto professors with world-leading expertise in RNA biology, nervous system development, and stem cell research. James Ellis will conduct studies on regulation of RNA stability and translation into proteins in pluripotent stem cells and their progeny during neurodevelopment and disease. Ben Blencowe will define RNA alternative splicing profiles that identify neuronal subtypes from specific brain regions and elucidate the regulatory modules that control these processes. Computational biology required to predict RBPs that control modules will be led by Quaid Morris. Freda Miller will discover novel RBP interactions with a translational repression complex and utilize this knowledge to enhance methods to specify neuron fate and to induce production of new-born neurons in vivo as a crucial step towards endogenous repair. John Calarco will decipher the map of RBP expression at single neuron resolution and test the role of RBPs in translational repression. The deliverables are discovery-driven findings of RNA biology that result in novel resources for identifying and specifying types of neurons, thereby enabling improved stem cell differentiation methods and induction of endogenous repair. This team is globally competitive and has an extensive record of discoveries that have transformed our knowledge of post-transcriptional regulatory mechanisms. The proposed research will result in novel intellectual property and be clinically translatable into stem cell based methods for use in drug testing and regenerative medicine.

Lead Investigator:

Cindi Morshead
Division of Anatomy, Department of Surgery, University of Toronto

Co-Investigators:

Andras Nagy, Molly Shoichet, Nir Lipsman

Project Description: Stroke is a leading cause of death and disability worldwide. There are no current treatments to repair the stroke-injured brain and promote recovery. Recovery of lost brain function after stroke involves relearning skills based on the ability of the nervous system to undergo structural and functional changes in response to new experiences, a phenomenon called neuroplasticity. Research is focused on developing new ways to encourage neuroplasticity, and stem cell based therapies offer promise in this area. Indeed, stem cell transplantation has shown some promise in animal models of stroke. However, greater insight into the mechanisms that underlie the success of neural stem cells transplantation is needed. This research team has come together to solve an unmet challenge, namely to find a source of stem cells that can be used safely and to understand the mechanisms by which transplanted cells promote neural repair. The group’s pioneering work will enable this project to engineer cells and cell delivery materials to further understanding of the mechanisms underlying the success of cell transplantation paradigms. The combined expertise in stem cell biology, tissue engineering, biomaterials, stroke and neuroplasticity, will allow the team to:

• use genetic tools to generate clinically relevant stem cell populations for transplantation;
• bioengineer materials that encourage cell survival and cell integration in the injured brain;
• use novel approaches to gain insight into the underlying mechanisms that promote recovery; and
• create a roadmap to the clinic for cell-based strategies to treat stroke.

Lead Investigator:

Molly Shoichet
Department of Chemical Engineering and Applied Chemistry, Institute of Biomaterials and Biomedical Engineering, Department of Chemistry & Institute of Medical Science, University of Toronto

Co-Investigators:

Derek van der Kooy, Gary Bader, Shana Kelley, Ted Sargent, Valerie Wallace, Robert Devenyi

Project Description: Age-related macular degeneration (AMD) is one of the leading causes of blindness in developed countries. AMD is characterized by the degeneration of cone photoreceptors in the retina, the cells responsible for central pattern (e.g. reading) and colour vision. This degeneration is due to pathological changes in the cone photoreceptors themselves, the retinal pigment epithelial (RPE) cells, and/or the rod photoreceptors. Current therapies for AMD are effective in slowing degeneration and the onset of blindness, but cannot restore lost vision. The goal of this project is to use cell therapy to restore vision loss in AMD patients. The team proposes that cone transplantation, either alone or in combination with rods and/or RPE cells, will restore central vision, and proposes to study this first in mice and ultimately in patients with AMD. To achieve this goal, a team of clinical and basic researchers has been assembled with the expertise required for success. This internationally renowned team brings their expertise to achieve success in rod and cone photoreceptor derivation, computational biology, cell purification, bioengineering, rodent models of disease and the clinic. The team will develop procedures for the efficient identification of rod and cone photoreceptor specific progenitors from stem cells and their differentiation and purification into human rod and cone photoreceptors. Simultaneously, it will determine the optimal conditions for cone engraftment into blind hosts and measure visual improvement in rodents. Ultimately, it will require a vitreous substitute that will improve retinal re-attachment after transplant surgery and thus will pursue an innovative biomaterial strategy to this end.

Return to top of page

Lead Investigator:

Cristina Nostro
McEwen Centre for Regenerative Medicine & Toronto General Research Institute, University Health Network
Department of Physiology, University of Toronto

Co-Investigators:

Sara Vasconcelos, Derek van der Kooy, Mark Cattral

Project Description: Type 1 Diabetes (T1D) results from the loss of insulin-producing b-cells, which are located in the islets of Langerhans in the pancreas. Patients with T1D are completely dependent on insulin administration for their survival. Despite advances in diabetes care, insulin formulations, and insulin delivery systems, insulin therapy fails to prevent high blood glucose levels, which can lead to serious complications such as kidney disease, amputations and blindness. As a consequence, there is intense interest in developing alternative therapies to restore b-cell function. Transplantation of insulin-producing tissue (pancreas or isolated islets) is an effective treatment for selected patients. However, the limited availability of deceased donor pancreata limits its application, especially if considering that most patients undergoing islet transplantation require more than one islet infusion, due to the 50 to 60 per cent loss of islets immediately following transplantation. Stem cell-derived b-cells offer the potential of an unlimited supply of cells for T1D therapy. Knowledge of the culture conditions required to promote b-cell generation from stem cells has grown exponentially over the last decade. This project addresses the critical issues of cell delivery and function after transplantation. This proposal brings together an established multidisciplinary team to understand the role played by vascular and neural connection and evaluate whether including these components at the time of transplantation improves the long-term survival and function of stem cell-derived b-cells. It is expected that the proposed approach will increase the efficiency of transplantation and provide a crucial framework for implementing stem cell-derived b-cell therapy for T1D treatment.

Lead Investigator:

JC Zúñiga-Pflücker
Biological Sciences, Sunnybrook Research Institute
Department of Immunology, University of Toronto

Co-Investigators:

Naoto Hirano, Tracy McGaha, David Brooks, Andras Nagy, Cristina Nostro, Derek van der Kooy

Project Description: The immune system remains one of the major barriers to effectively translate the advances in the generation of stem cell-derived tissues for regenerative medicine applications. New immunomodulation therapies such as using regulatory T-cells or tolerogenic/biomaterial activated innate immune cells (macrophages/dendritic cells) are needed. There is also a need to induce/produce tolerogenic innate cells, macrophages and dendritic cells (DCs) to suppress the pathogenic T cells and promote Treg subsets. The proposed immune suppression strategies together with the ability to generate donor cell lines with decreased immunogenicity and will likely lead to improved and more effective allograft therapies. The goal is to take advantage of the immune system and its regulation as key components to controlling chronic disease and inflammation, activating regeneration and allowing for robust cell, tissue and organ transplantation. There is a critical barrier to this above vision: deriving and testing the safety of individual iPSC lines takes an incredible amount of time and resources, and creating one for each patient who needs a cell-based therapy is economically and practically unrealistic. This team proposes a solution by engineering an iPSC line to expresses local immunomodulatory genes. The expression of these transgenes makes the cells “cloaked”, which prevents immune recognition and rejection when grafted in allogeneic hosts. Cloaked cells would allow a single cell line to be used as a source of therapeutic cells. Ultimately, these transformative properties would overcome some of the most critical economic and biological barriers that will emerge in the future of cell-based therapies.

Return to top of page