Division of Experimental Therapeutics - Cardiovascular
Toronto General Research Institute (TGRI)
Keywords: heart failure, myocardial infarction, cell transplantation, stem cell differentiation, cell and gene therapy, angiogenesis, extracellular matrix, tissue engineering |
My research group in the Division of Cardiovascular Surgery focuses on translational research to apply new insights discovered through basic science research to clinical applications for cardiac regeneration and repair. Our research areas are:
1) Cell transplantation
into damaged myocardial tissue to regenerate myocardium and restore cardiac function.
2) Tissue engineering
to create a muscle graft using autologous cells in combination with biomaterials for repair of cardiac defects.
In 1996, I demonstrated that cardiac function after myocardial infarction could be restored by transplantation of healthy cells. Since then we have performed a number of studies to identify the optimal conditions to translate this technique into clinical applications. We also identified several possible mechanisms for implanted cells to regenerate injured myocardium to restore cardiac function. Early clinical data suggested that aged patients require enhanced cell therapy. Our current research therefore focuses on developing clinically relevant improvements to cell transplantation for cardiac treatment.
1. Effectiveness of cell transplantation in aged individuals
: We recently demonstrated that the ability to effectively respond to cell transplantation is impaired in aged individuals, which has led us to studies to identify possible techniques for rejuvenating recipients to enhance their responsiveness.
We also determined that the number and quality of stem cells in aged patients was not sufficient for cardiac regeneration, which led us to find the optimal cell types for transplantation. We have explored the possibility of rejuvenating endogenous stem cells from aged patients to enhance their ability to be recruited to the injured heart and to regenerate injured tissue. In addition, we are examining methods for maximizing the effectiveness of allogeneic young cells for cell transplantation in aged hearts. As part of our search for the optimal cell type, we identified hemangioblasts in adult uterine tissue that may have potential for both transplantation and endogenous repair.
2. Therapeutic factors that improve cell transplantation
: We have identified a number of biological factors that have beneficial effects on implanted cell survival and wound healing in the damaged heart. To effectively delivery these molecules to the injured tissue, we have developed a non-invasive targeted delivery technique. Using ultrasound targeted microbubble destruction, we can repeatedly deliver regenerative molecules to an injured heart. As another technique for delivery of regenerative molecules, we synthesized a temperature sensitive hydrogel, which is liquid at room temperature and a gel at body temperature. We are currently using these two delivery systems to deliver regenerative factors into injured tissue for cardiac repair.
3. Tracking cell retention
: We have developed molecular imaging techniques to label and track transplanted cells. This non-invasive method has allowed us to determine the optimal methods of implantation to maximize cell retention.
Some of the advances I have made in cell transplantation are currently being used to treat cardiac patients in clinical trials.
A great challenge in growing cells to repair cardiac defects is encouraging them to grow as an integrated three-dimensional structure. We have developed biodegradable materials that support the growth of cells in three-dimensions and have improved heart function by using these cell-seeded materials to surgically replace damaged heart tissue. This technique is being refined to fully realize the potential of these grafts. We recently showed that the inclusion of the regenerative factors mentioned above enhanced the effectiveness of these grafts for cardiac repair.
These projects are supported by the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Ontario.
Zhuo Y, Li SH, Chen MS, Wu J, Kinkaid HY, Fazel S, Weisel RD, Li RK. Aging impairs the angiogenic response to ischemic injury and the activity of implanted cells: combined consequences for cell therapy in older recipients. J Thorac Cardiovasc Surg. 2010 May;139(5):1286-94.
- Professor, Department of Surgery, Division of Cardiovascular Surgery, University of Toronto
Huang XP, Sun Z, Miyagi Y, McDonald Kinkaid H, Zhang L, Weisel RD, Li RK. Differentiation of allogeneic mesenchymal stem cells induces immunogenicity and limits their long-term benefits for myocardial repair. Circulation. 2010 Dec 7;122(23):2419-29.
Sun Z, Zhang Y, Brunt KR, Wu J, Li SH, Fazel S, Weisel RD, Keating A, Li RK. An adult uterine hemangioblast: evidence for extramedullary self-renewal and clonal bilineage potential. Blood. 2010 Oct 21;116(16):2932-41.
Fujii H, Li SH, Wu J, Miyagi Y, Yau TM, Rakowski H, Egashira K, Guo J, Weisel RD, Li RK. Repeated and targeted transfer of angiogenic plasmids into the infarcted rat heart via ultrasound targeted microbubble destruction enhances cardiac repair. Eur Heart J. 2011 Jan 8.
Li SH, Lai TY, Sun Z, Han M, Moriyama E, Wilson B, Fazel S, Weisel RD, Yau T, Wu JC, Li RK. Tracking cardiac engraftment and distribution of implanted bone marrow cells: Comparing intra-aortic, intravenous, and intramyocardial delivery. J Thorac Cardiovasc Surg. 2009 May;137(5):1225-33.
Miyagi Y, Chiu LL, Cimini M, Weisel RD, Radisic M, Li RK. Biodegradable collagen patch with covalently immobilized VEGF for myocardial repair. Biomaterials. 2011 Feb;32(5):1280-90.
Wu J, Zeng F, Huang XP, Chung JC, Konecny F, Weisel RD, Li RK. Infarct stabilization and cardiac repair with a VEGF-conjugated, injectable hydrogel. Biomaterials. 2011 Jan;32(2):579-86.
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