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OUR RESEARCH
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The Cardiac Translational Research Laboratory is located within the University of Ottawa Heart Institute, Canada’s largest cardiovascular health centre. The institute serves a catchment area of more than 2 million people which translates into caring for 100,000+ patients a year.
The lab is integral to these efforts as we focus on translating fundamental biological principles to the clinical setting. Techniques range from the molecular to the multicellular level with extensive cross fertilization amongst projects. Current projects within the lab revolve about 2 themes, namely: 1. Stimulation of endogenous repair using biological therapies Unlike nematodes and reptiles, mammals possess a very limited capacity for self repair. Heart tissue turnover dwindles after childbirth such that the yearly replacement of heart cells languishes between 0.5 and 2%. Given that 600,000 Canadians suffer from heart failure, this limited reserve is clearly insufficient to replace the billions of cardiomyocytes lost after cardiac injury. With an aging population living longer, heart failure is on the rise and represents a looming epidemic. These findings rationalize focus on novel means to repair, re-vascularize and restore damaged hearts.
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To meet this challenge, we are exploring the impact of biological therapies on heart function. We have developed an animal product-free means of growing human stem cells in clinical grade cell manufacturing facilities (doi.org/10.1186/s13287-019-1418-3); thus, producing a cell product ready for delivery to patients. After these cells are injected into injured hearts, most cells lodge only briefly and are cleared within a few days. While resident in the injured heart, stem cells release a wide variety of anti-inflammatory cytokines, growth factors and extracellular vesicles that reduce inflammation and promote endogenous repair (doi.org/10.1002/stem.2910 & doi.org/10.1080/14712598.2017.1346080). This effect is referred to as a paracrine-mediated repair and, as we have found, is highly dependent on the soluble signals produced by transplanted cells.
Injection of blood and heart stem cells into injured hearts improves healing after injury. The unique pro-healing cytokines produced by each cell type synergizes to stimulate growth of new heart tissue better than either therapy alone (doi.org/10.1161/CIRCULATIONAHA.112.000374). The paracrine product secreted by these transplanted cells is critical. If we block production of key cytokines that promote repair (such as interleukin 6), the pro-healing effect of cell treatment is reduced (doi.org/10.7150/thno.19435). The converse is also true. If we use genetic engineering to over-express key pro-healing cytokines in cells before transplantation, endogenous repair is increased (doi.org/10.1002/stem.2373 & doi.org/10.1161/JAHA.115.002104). We have shown that the “health” of a cell is a key determinant of how effective they will be at improving heart function. If we use cells donated by patients with diabetes (doi.org/10.1161/CIRCULATIONAHA.113.007908), advanced age (doi.org/10.1111/acel.13174) or multiple medical illnesses (doi.org/10.1186/s13287-016-0321-4), the paracrine signature is reduced, and the effects of cell treatment are blunted. But invasive bioengineering may not be needed to enhance a biological therapy. Recently, we have found that altering the properties of inert biomaterials that cocoon cells can increase the paracrine repertoire and promote greater endogenous repair (doi.org/10.1021/acsnano.7b08881). Akin to a hockey team, stem cells also work better when they are working together. Using microfluidic-based cocooning, we recently found that cell to cell contact can be adjusted to increase cytokine and extracellular vesicle production and potency (doi.org/10.1016/j.biomaterials.2020.120010). 
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In the end, Humans are biological systems. Although mechanical and medical therapies have historically been used to modify function and treat patients, sustained improvements will only be realized by altering the biological system. Paracrine therapies provide the means to adjust a human meme. But tissues and organs are complex and not all the salutary benefits of a paracrine therapy can be reproduced by a single component. There is no magic bullet. As such, our approach works towards guiding the 20,000+ molecules needed in different combinations to maximize benefits. With support from the Canadian Institute of Health Research and the Heart and Stroke Foundation of Canada, we are investigating the effects of biological therapies on models of cardiac arrhythmias, cardiac damage and cardiac inflammation.
2. Modeling sudden cardiac death using induced pluripotent stem cells We are all made of trillions of small building blocks called cells. Each cell has its own job and each cell contains a copy of instructions called DNA that tells each cell what to do. Sometimes the DNA blueprint for cells gets changed from normal. These changes can influence how cells function and may result in disease. Some DNA changes can disturb the electrical coordination of the heart. This is very important because waves of electricity between cells stimulate and synchronize every heartbeat. Even small disruptions can result in cardiac arrest and, very possibly, death. Oftentimes, these “inherited arrhythmias” are first detected only after a child or teenager is lucky enough to survive a cardiac arrest. Over the past 20 years, Canadian doctors have become world leaders in treating patients with inherited arrhythmias. Years of work have led to the development of many successful treatment protocols used worldwide. But these protocols are not curative because our understanding of how these DNA changes result in deadly heart rhythms has lagged far behind the clinical science and now limits our ability to discover new therapies. Human heart tissue derived from a blood sample beating in a cell culture dish |
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Recently, we developed techniques to grow heart tissue in a dish from blood cells (doi.org/10.1080/14712598.2019.1575359). In this work, we are using these techniques to build a central heart tissue repository from blood samples donated by patients with inherited arrhythmias. To accomplish this, we have brought together doctors that treat patients with scientists that study how cells function to understand how changes in the DNA code account for deadly heart rhythms.
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To accomplish this, we have partnered with the Canadian Sudden Arrhythmia Death Syndromes Foundation and the First Nations people affected by inherited arrhythmias. With their help, this work will provide the critical “proof of concept” data that our cooperative Canadian initiative can work. This experience will then be used to secure federal and provincial funding to expand and sustain the program. As the number of samples grows, we believe this program will become self sustaining as these valuable tissue banks will undoubtedly play key roles in developing new therapies and detecting unexpected side effects from medicines.
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