Deciphering and manipulating cell-specific regulatory networks to produce therapeutic designer cells
Project PI: Jason Fish
Department of Laboratory Medicine and Pathobiology, University of Toronto
Co-PIs: 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.
New technologies for high-performance stem cell cultures
Project PI: Shana Kelley
Department of Pharmaceutical Sciences, Department of Biochemistry, Department of Chemistry and Institute of Biomaterials & Bioengineering, University of Toronto
Co-PIs: 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.
Organ replacement, repair and regeneration
Project PI: Shaf Keshavjee
Toronto General Research Institute, University Health Network
Division of Thoracic Surgery and Institute of Biomaterials & Bioengineering, University of Toronto
Co-PIs: 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.
Characterization of the neurovascular islet “niche” and its role on b-cell function and maturation
Project PI: Cristina Nostro
McEwen Centre for Regenerative Medicine & Toronto General Research Institute, University Health Network
Department of Physiology, University of Toronto
Co-PIs: 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.
Decellularization and recellularization for lung and airway regeneration
Project PI: Tom Waddell
Toronto General Research Institute, University Health Network
Division of Thoracic Surgery & Institute of Biomaterials & Bioengineering, University of Toronto
Co-PIs: 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.