The main goal of the Cardiovascular Tissue Engineering Laboratory, under the direction of Erik Suuronen, PhD, is to develop tissue engineering and cell-based therapeutic approaches for the treatment of cardiac injury and disease.
Despite major advances in therapy, there are still a significant number of patients identified with the coronary artery disease who die of it. This is because over the long term, current treatments are not perfect. They do not cure the disease and they can fail over time.
In recent years, cell therapy has emerged as a promising new approach for the treatment of cardiovascular diseases. For example, there is much optimism that this approach will one day constitute the best way to treat patients with blocked arteries around the heart. However, the science is quite complex, and translation of the research findings into the clinic is likely to require strategies to enhance the function of the therapeutic cells, and the patient’s response to them. With this in mind, tissue engineering may offer one way to help direct the repair process. Tissue engineering can be described as a combination of cells, engineering and materials methods for use as replacement tissues (either temporary or permanent) for damaged or diseased body parts.
The lab is also interested in how the body’s own stem cells respond when the heart is damaged, and how to enhance this response. Strategies to improve the host stem cell response include the use of biomaterials designed to mobilize and recruit these repair cells. Other research being performed in the lab includes the investigation of biomaterial scaffolds and stem/progenitor cell transplantation for promoting angiogenesis in the heart in order to restore blood flow to damaged tissue and improve its function. In addition, projects are underway to develop therapies to treat diabetes and its associated cardiovascular complications. It is hoped that this research will constitute a major step towards making cell and tissue engineering therapies more effective for patients with heart disease.
The Cardiovascular Tissue Engineering Laboratory is affiliated with the Biomaterials and Regeneration Research Program in the Division of Cardiac Surgery. The Lab provides training opportunities for students to perform research in pursuit of their degrees at all levels with the University of Ottawa. Funding for the lab is provided by the Canadian Institutes of Health Research (CIHR), the Heart & Stroke Foundation (HSF), the Natural Sciences and Engineering Research Council (NSERC), the Juvenile Diabetes Research Foundation and the Ministry of Research and Innovation.
Current ongoing projects in the laboratory:
- Biomaterial and Cell-based Cardiac Therapies
- Mechanisms of Cell-Matrix Interaction
- Biomaterials for Progenitor Cell Recruitment
- Regenerative Approaches for the Treatment of Diabetes and Associated Cardiovascular Complications
- Molecular Function and Imaging Program
Biomaterial and Cell-based Cardiac Therapy
Transplanted cells (arrows) incorporating into the wall of a blood vessel.
The clinical feasibility and safety of cell therapy for treating myocardial infarction has been demonstrated. Despite this, the observed functional improvement with cell therapy has been modest. The lack of a more significant benefit can be attributed, in part, to the low survival, engraftment and function of transplanted cells. In addition, the reparative cells from diseased patients often have reduced function. Therefore strategies are needed to improve transplanted cell retention and therapeutic potency. A possible solution to overcome these hurdles is to use of tissue engineered biomaterials. This involves the provision of a biomaterial scaffold to promote transplanted cell engraftment and to guide the regenerative processes.
Small animal PET images showing better retention of transplanted cells when delivered to the tissue using a matrix
In one project, Dr. Suuronen and Marc Ruel, MD, are leading a team investigating new ways to grow and deliver a special type of cell into the heart. The cells of interest, termed endothelial progenitor cells, have the potential to create new arteries and can be obtained from a blood sample. New culture techniques are being used to grow and expand the number of these cells and ways of re-delivering them into the damaged heart are being developed. For this, various tissue engineered matrix materials are being tested. This research also aims to examine how the matrix may be used to enhance the survival, engraftment and function of transplanted cells.
In addition to enhancing transplanted cell effects, the matrix is being evaluated for its ability to address the fact that tissues of patients requiring treatment are more aged and diseased, which negatively affects the heart’s ability to respond to therapy. We are investigating the use of tissue engineered materials to improve the condition of the host tissue by reducing inflammation, cell death, and remodeling of the heart. In collaboration with Katey Rayner, PhD, the lab is examining microRNA signaling that may be critical in directing the protective effects of matrix therapy. This information will provide future targets for augmenting the therapeutic potential of the matrix. It is our goal for such novel tissue engineering strategies to eventually make humans more responsive to regenerative therapies.
Mechanisms of Cell-matrix Interaction
Understanding how cells respond to their extracellular matrix (ECM) environment could enable us to manipulate and enhance cell functions and better guide tissue regeneration in diseased tissue. Integrins are cell surface proteins that are the main link for communication between the extracellular environment and the inside of the cell. The interaction of integrins with extracellular proteins activates a variety of signaling pathways that regulate a range of cellular functions including proliferation, differentiation, migration, survival, and adhesion. We are interested in learning how different proteins in the cell’s environment stimulate different cell functions in healthy and diseased tissues. With this information, we can design strategies to restore important signaling that may be altered in disease by manipulating the cells and/or their environment. This knowledge will also serve to develop ECM-like biomaterials that can be administered to damaged hearts to provide an environment that is more supportive of regeneration.
Clusters of CD34+ cells expressing integrin α5 (green) after culture on a collagen matrix
Biomaterials for Progenitor Cell Recruitment
In this research, we are developing new strategies to attract regenerative cells from the circulation into the heart. The cells of interest are stem and progenitor cells that are released from the bone marrow into the blood, and have the potential to create new arteries. Biomaterials are being designed to release factors that will increase mobilization of these cells and attract them to the heart. These matrix materials, referred to as “enhanced matrices”, also contain specific sites onto which the recruited cells attach. Such materials are expected to stimulate the recruited cells and repair processes to regenerate new arteries. This will restore the blood supply to the damaged areas of the heart.
Repairing Damaged Muscle: (A) A collagen matrix containing sialyl LewisX is injected at the site of damaged muscle tissue, where it gels to form a “smart” scaffold. (B) The presence of sialyl LewisX attracts progenitor cells to the site and binds with their L-selectin receptors. The progenitor cells take up residence in the scaffold, where they send out signals to attract more repair cells, and new blood vessels are generated. (C) The new vessels provide oxygenated blood to growing muscle tissue, repairing the damage caused by ischemia
A story on the state of regenerative medicine for growing a new heart, including details on this research can be read in a Maclean’s article published in February 2009.
Regenerative Approaches for the Treatment of Diabetes and its Associated Cardiovascular Complications
Vascular repair in the ischemic muscle of diabetic mice is superior when a toxic product called methylglyoxal is removed from the tissue (GLO1-diabetic). This is partly because more repair cells are recruited from the bone marrow (yellow).
Diabetes constitutes a major health problem and the global prevalence of the disease is expected to rise in coming years. Approximately 80% of diabetic mortality is a result of heart disease or stroke. Diabetics can suffer from circulation problems, which may include peripheral artery disease, and reduced blood flow to the heart ultimately leading to heart failure. The body’s natural response is to attempt to resupply the tissue by growing new blood vessels; however this mechanism is defective in diabetics. Therefore, we aim to identify possible links between the diabetic condition and the loss of vasculature. Toxic products produced in the body contribute to the harmful effects of diabetes, particularly vascular abnormalities. We are examining whether a reduced amount of these toxic products will help reverse the defective blood vessel growth found in diabetes. In particular, we are examining the effect of the toxic products on the function of progenitor cells, which act in the blood vessel regeneration process. We are also examining the effects of these toxic products on the development of diabetic cardiomyopathy, a disorder of the heart muscle.
Molecular Function and Imaging (MFI) Program
This is a program under the direction of Rob Beanlands, MD. Principal investigators collaborating in this Program are Drs. Erik Suuronen, Marc Ruel (cardiac surgery), Rob deKemp (imaging physics), and Mary-Ellen Harper (bioenergetics). The Program has grown from about 15 trainees in 2006 to over 50 graduate students, post-doctoral fellows and medical residents and fellows in 2013. The central theme of this group is the investigation of metabolic and cellular function alterations in the pathophysiology of cardiovascular diseases that contribute to myocardial dysfunction and heart failure and their response to therapeutic interventions. Although various evaluation methods are utilized within this group, the central link rests in the unique molecular imaging capabilities of positron emission tomography (PET). The Program is also focused on its transdisciplinary training environment, which is in place for our students who are being nurtured for future leadership positions. Among other initiatives, trainees in our group are being co-supervised, engaging in cross-disciplinary collaborative research, with structured courses and student-based scientific retreats.
- A. Ahmadi, S. Thorn, M. E. I. Alarcon, Kordos, D. T. Padavan, T. Hadizad, G. O. Cron, R. S. Beanlands, J. N. DaSilva, M. Ruel, R. A. deKemp and E. J. Suuronen. PET imaging of a collagen matrix reveals its effective injection and targeted retention in a mouse model of myocardial infarction. Biomaterials 2015;49:18-26.
- N. J. R. Blackburn, T. Sofrenovic, D. Kuraitis, A. Ahmadi, B. McNeill, C. Deng, K. J. Rayner, Z. Zhong, M. Ruel and E. J. Suuronen. Timing underpins the benefits associated with injectable hydrogel therapies for the treatment of myocardial infarction. Biomaterials 2015;39:182-92.
- B. McNeill, B. Vulesevic, A. Ostojic, M. Ruel and E. J. Suuronen. Collagen matrix-induced integrin αVβ3 expression in circulating angiogenic cells targeted by matricellular protein CCN1 to enhance their function. FASEB J 2014; Dec 2 [e-pub ahead of print].
- C. G. Palii, B. Vulesevic, S. Fraineau, E. Pranckeviciene, A. J. Griffith, A. Chu, H. Faralli, Y. Li, B. McNeill, J. Sun, T. J. Perkins, F. J. Dilworth, C. Perez-Iratxeta, E. J. Suuronen, D. Allan and M. Brand. Trichostatin A enhances the vascular repair function of injected human endothelial progenitors by increasing the expression of TAL1-dependent genes. Cell Stem Cell 2014;14:644-57.
- A. Ahmadi, B. McNeill, B. Vulesevic, M. Kordos, L. Mesana, S. Thorn, J. M. Renaud, E. Manthorp, D. Kuraitis, H. Toeg, T. G. Mesana, D. R. Davis, R. S. Beanlands, J. N. DaSilva, R. A. deKemp, M. Ruel and E. J. Suuronen. The role of integrin α2 in cell and matrix therapy that improves perfusion, viability and function of infarcted myocardium. Biomaterials 2014;35:4749-58.
- B. Vulesevic, B. McNeill, M. Geoffrion, D. Kuraitis, J. E. McBane, M. Lochhead, B. C. Vanderhyden, G. S. Korbutt, R. W. Milne and E. J. Suuronen. Glyoxalase-1 over-expression in the bone marrow reverses defective neovascularization in streptozotocin-induced diabetic mice. Cardiovasc Res 2014;101:306-16.
Current Team Members
Graduate and Post-doctoral fellows:
Bora Nadlacki, BSc, Master’s student
Branka Vulesevic, DVM, MSc, Doctoral student
Brian McNeill, PhD, Post-doctoral fellow
James Podrebarac, BSc, Master’s student
Kay Maeda, MD, PhD, Post-doctoral fellow
Nick Blackburn, BSc, Doctoral student
Zachary Lister, BSc, Master’s student
Joanne Joseph, Honour’s student
Thara Ali, Honour’s student
Richard Seymour, BSc, Animal research technician
Past Team Members
- Dr. Ali Ahmadi (Doctoral student)
- Anna Badner (Honour's student)
- Helene Chiarella-Redfern (Master’s student)
- Dr. Chao Deng (Post-doctoral fellow)
- Christine Eisner (Honour's student)
- Ben Engel (Co-op student)
- Carine Ghem (Visiting PhD student)
- Khrystyna Herasym (Honour's student)
- Chenchen Hou (Master's student)
- Drew Kuraitis (Doctoral student)
- Marina Lochhead (Co-op student)
- Rafaela Machado (International summer student)
- Emily Manthorp (Medical student)
- Jenelle Marier (Master's student)
- Dr. Eva Mathieu (Post-doctoral fellow)
- Dr. Joanne McBane (Post-doctoral fellow)
- Kimberly McEwan (Master’s student)
- Angela Melhuish (Summer student)
- Laura Mesana (Summer student)
- Kyra Nicholson (Summer student)
- Nadya Nossova (Honour's student)
- Aleksandra Ostojic (Master’s student)
- Dr. Donna Padavan (Post-doctoral fellow)
- Jennifer Poelstra (Co-op student)
- Zorica Prostran (Honour's student)
- Eleni Ramphos (Summer student)
- Julia Ranieri (Master’s student)
- Tanja Sofrenovic (Master's student)
- Zahra Sharif (Medical summer student)
- Hadi Toeg (Medical summer student)
- Lida Tohidi (Honour's student)
- Jeffrey Yates (Honour's student)
- Dr. Pingchuan Zhang (Post-doctoral fellow)
- Chris Zuliani (Summer student)