| Laboratory Medicine and Pathobiology --- University of Toronto

Ren-Ke Li’s research focuses on translational research to apply new insights discovered through basic science research to clinical applications for heart regeneration and repair after myocardial infarction. Research areas are: 1) Cell transplantation into damaged tissue to regenerate myocardium and restore heart function. 2) Tissue engineering to create a muscle graft using stem cells and biomaterials for repair of cardiac defects.

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Research

My research focuses on the development of novel therapies for repairing and regenerating the injured myocardium and improving cardiac function after a myocardial infarction (MI). Cardiomyocyte loss after an MI initiates a cascade of events which frequently results in progressive heart failure despite the best medical, interventional and surgical interventions. Novel therapies are needed to treat these patients and prevent progressive deterioration of cardiac function.

Cell transplantation from bench to bedside

Since 1993 I have focused on cellular therapy to prevent progressive heart failure. My initial studies described the transplantation of cardiac muscle cells into a myocardial scar which limited ventricular dilatation, stimulated angiogenesis and improved heart function. In 1996, I demonstrated for the first time that transplanted cardiomyocytes can improve heart function. Since then, I have performed many studies in small and large animal models to evaluate a variety of cardiac cell transplantation approaches. My preclinical studies demonstrate the safety and efficacy of cell transplantation to restore heart function. In collaboration with cardiac surgeons, we translated this new treatment to the clinic. Over the past 20 years, I have published more than 200 peer-reviewed papers on cell therapy, which has been translated from bench to bedside. The following is a summary of my most significant contributions that demonstrate my expertise and highlights the network of experts in my program:

1. Cell transplantation to restore heart function after injury: I transplanted cardiomyocytes, smooth muscle cells, heart cells and bone marrow (BM) cells into myocardial scar tissue and demonstrated that the implanted cells replace the scar with muscle tissue, augment cardiac function and prevent progressive heart failure.

2. Identification of the mechanisms responsible for the beneficial effects of cell therapy: Muscle formation: The implanted muscle cells formed muscle-like tissue in the fibrotic scar tissue which prevented ventricular dilation and restored heart function. Angiogenesis: Implantation of stem cells (SCs) into the damaged tissue produced less muscle, but stimulated a more extensive network of new capillaries and arterioles. I discovered and established that the benefits achieved were the result of the secretion of paracrine factors by the transplanted cells. Matrix modulation: I found that cells implanted into scar tissue decreased matrix metalloproteinase (MMP) activity by increasing tissue levels of tissue inhibitor of MMPs. I discovered and confirmed that the rebalancing of protease and protease inhibitor activities prevent myocardial matrix degradation and heart failure.

3. Evaluation of the safety and efficacy of cell therapy for clinical applications: To establish the potential of cell therapy for clinical application, we performed cell transplantation in a pig model of MI. Cardiac function was evaluated using clinically-relevant technology (echocardiography and SPECT MIBI). We demonstrated that cell therapy was safe and effective to prevent cardiac dysfunction.

4. Identification of aging as a major limitation for the clinical results of cell therapy: The results of the clinical trials did not produce the significant beneficial effects that we found in our preclinical studies. These incongruent effects could be a result of multiple factors. However, we found that the quantity and quality of SCs in aged individuals with heart disease was much lower than those in younger patients, which could be a major contributor to the reduced efficacy of cell therapy in aged patients.

5. Rejuvenation, a new concept for stem cell therapy for aged patients: We demonstrated that BM SC dysfunction diminished cardiac repair after MI. We created BM chimeras by rejuvenating aged mice with young BM SCs. These rejuvenated mice had a greater cardiac repair capacity compared to non-rejuvenated mice. These data suggest a new direction for cell therapy: rejuvenation of cells and the host to enhance the efficacy of cell therapy in aged patients.

Development of a platform for non-invasive, repetitive, targeted and double-targeted gene delivery for cardiac regeneration and cell therapy. We have created an antibody-conjugated, cationic microbubble to enhance targeted gene delivery.

Creation of cardiac tissue for repair of congenital heart defects

Congenital heart disease affects ~1% of newborns, many of which require surgical intervention with the insertion of a patch. Most biomaterial patches becomes stiff and scarred and do not grow with the children. Tissue-engineered grafts have the potential to reduce mortality and improve the quality of life of these patients. We have created cytokine-enriched biomaterials to enhance cell survival and tissue formation by immobilizing multiple cytokines onto biomaterials.

Professor

Dr. Ren-Ke Li, MD, PhD is a Professor of Medicine in the Department of Surgery, Division of Cardiac Surgery at the University of Toronto. Dr. Li is a Senior Scientist at the Toronto General Research Institute, University Health Network working in the field of stem cell transplantation and tissue engineering. Dr. Li is the Canada Research Chair in Cardiac Regeneration (Tier 1) of the Canadian Institutes of Health Research and was a Career Investigator of the Heart and Stroke Foundation of Canada.

Dr. Li has been on the forefront in the field of cell transplantation and tissue engineering. In 1996, he published the first demonstration that cells transplanted into injured heart can form a muscle tissue, regenerated damaged hear, and improved heart function. Recently, his group has defined optimal cell types for transplantation, and described the optimal conditions under which the transplanted cells can achieve the most efficient repair. Currently, his research group is attempting to rejuvenate aged individual using young stem cells to improve repair and regenerative capacity of aged patients. He also developed a platform for targeted gene or regenerative factor delivery for targeted tissue/organ therapy.

Dr. Li has published 206 peer-reviewed papers and his work has appeared in high impact journals including Journal of Clinical Investigation, Circulation, Circulation Research, Journal American College Cardiology, European Heart Journal. Dr. Li has been invited to contribute several commentaries and viewpoint articles and is an international opinion leader in his field.

Lab

Our Cardiovascular Research laboratory located at the Toronto General Research Institute (TGRI) within UHN. The research laboratory comprises 1) a molecular biology research laboratory with advanced equipment and technologies to determine the mechanisms of cardiac regeneration, including light and fluorescence microscopes for extensive immunohistochemical evaluations; 2) a cell culture facility with two rooms for experimental and preclinical studies; and 3) an office space for my research team, including clinical and postdoctoral fellows, students and technicians. 4) I also lead the Preclinical Center for Cardiac Regeneration, a small animal surgical facility in the Max Bell Research Centre. It is equipped with surgical tables, surgical microscope, and all other necessary instruments and supplies for acute and chronic studies.

Publications

See all Publications: PubMed

• Sun Z, Wu J, Li SH, Zhang Y, Xaymardan M, Wen XY, Weisel RD, Keating A, Li R-K. Uterine-derived stem cells reconstitute the bone marrow of irradiated mice. Stem Cells Dev. 2015 Apr 15;24(8):938-47.

• Guo J, Zhang Y, Mihic A, Li SH, SunZ, Shao Z, Wu J, Weisel RD, Li R-K. A secreted protein (Canopy 2, CNPY2) enhances angiogenesis and promotes smooth muscle cell migration and proliferation. Cardiovascular Research. 2015 Mar 1:105(3):383-93.

• Hatta K, Guo J, Ludke A, Dhingra S, Singh K, Huang ML, Weisel RD, Li R-K. Expression of CNPY2 in mouse tissues: Quantification and localization. PLoS One. 2014 Nov 13;13;9(11):e111370.

• Witty A, Mihic A, Tam R, Fisher S, Mikryukov A, Shoichet M, Li R-K, Kattman S. The generation of the epicardial lineage from human pluripotent stem cells. Nature Biotechnology. 2014 Jul 25;32(10):1026-35.

• Sun X, Momen A, Wu J, Noyan H, Li R-K, Von Harsdorf R, Husain M. p27 protein protects metabolically stressed cardiomyocytes from apoptosis by promoting autophagy. J Biol Chem. 2014 Jun 13;289(24):16924-16935.

• Zhang L, Chen X, Sharma P, Moon M, Sheftel AD, Dawood F, Nghiem MP, Wu J, Li R-K, Gramolini AO, Sorensen PH, Penninger JM, Brumell JH, Liu PP. HACE1-dependent protein degradation provides cardiac protection in response to haemodynamic stress. Nature Communications. 2014 Mar 11;5:3430.

• Mihic A, Li J, Miyagi Y, Gagliardi M, Li SH, Zu J, Weisel RD, Keller G, Li R-K. The effect of cyclic stretch of maturation and 3D tissue formation of human embryonic stem cell-derived cardiomyocytes. Biomaterials. 2014 Mar 1;35(9):2798-808.

• Yan P, Chen KJ, Wu J, Sun L, Sung HW, Weisel RD, Xie J, Li R-K. The use of MMP2 antibody-conjugated cationic microbubble to target the ischemic myocardium, enhance Timp3 gene transfection and improve cardiac function. Biomaterials. 2014 Jan 1;35(3):1063-73.

• Wang YS, Li SH, Guo J, Mihic A, Wu J, Sun L, Davis K, Weisel RD, Li R-K. Role of miR-145 in cardiac myofibroblast differentiation. Journal of Molecular and Cellular Cardiology. 2014 Jan 1;66:94-105.

• Dhingra S, Li P, Huang XP, Guo J, Wu J, Mihic A, Li SH, Zang WF, Shen D, Weisel RD, Singal PK, Li R-K. Preserving prostaglandin E2 level prevents rejection of implanted allogeneic mesenchymal stem cells and restores postinfarction ventricular function. Circulation. 2013 Sep 10;128(11 Suppl 1):S69-78.

• Li P, Li SH, Wu J, Zang WF, Dhingra S, Sun L, Weisel RD, Li R-K. Interleukin-6 downregulation with mesenchymal stem cell differentiation results in loss of immunoprivilege. Journal of Cellular and Molecular Medicine. 2013 Sep 1;17(9):1136-45.

• El-Mounayri O, Mihic A, Shikatani EA, Gagliardi M, Steinbach SK, Dubois N, Dacosta R, Li R-K, Keller G, Husain M. Serum-free differentiation of functional human coronary-like vascular smooth muscle cells from embryonic stem cells. Circulation Research. 2013 Apr;98(1):125-35.

• Li S-H, Sun Z, Brunt KR, Shi X, Chen M-S, Weisel RD, Li R-K. Reconstitution of aged bone marrow with young cells repopulates cardiac-resident bone marrow derived progenitor cells and prevents cardiac dysfunction after a myocardial infarction. European Heart Journal. 2013 Apr;34(15):1157-67.

• Sun L, Huang CW, Wu J, Chen KJ, Li S-H, Weisel RD, Rakowski H, Sung HW, Li R-K. The use of cationic microbubbles to improve ultrasound-targeted gene delivery to the ischemic myocardium. Biomaterials. 2013 Mar;34(8):2107-16.

• Noyan-Ashraf MH, Shikatani EA, Schuiki I, Mukovozov I, Wu J, Li R-K, Volchuk A, Robinson LA, Billia F, Drucker DJ, Husain M. A glucagon-like peptide-1 analogue reverses the molecular pathology and cardiac dysfunction of a mouse model of obesity. Circulation. 2013 Jan;127(1):74-85.

• Kang K, Sun L, Xiao Y, Li S-H, Wu J, Guo J, Jiang S-L, Yang Lei, Yau TM, Weisel RD, Radisic M, Li R-K. Aged human cells rejuvenated by cytokine-enhancement of biomaterials for surgical ventricular restoration. Journal of the American College of Cardiology. 2012 Nov;60(21):2237-49.

• Brunt KR, Zhang Y, Mihic A, Li M, Li S-H, Xue P, Zhang W, Basmaji S, Tsang K, Weisel RD, Yau TM, Li R-K. Role of WNT/β-catenin signaling in rejuvenation myogenic differentiation of aged mesenchymal stem cells from cardiac patients. American Journal of Pathology. 2012 Sep;181(6):2067-78.

• Xaymardan M, Sun Z, Hatta K, Tsukashita M, Konecny F, Weisel RD, Li R-K. Uterine cells are recruited to the infarcted heart and improve cardiac outcomes in female rats. Journal of Molecular and Cellular Cardiology. 2012 Jun;52(6):1265-73.

• Wu J, Zeng F, Huang XP, Chung JCY, Konecny F, Weisel RD, Li R-K. Infarct stabilization and cardiac repair with a VEGF-conjugated, injectable hydrogel. Biomaterials. 2011 Jan;32(2):579-86.

• Fujii H, Li Sh, Wu J, Miuagi Y, Yau TM, Rakowski H, Egashira K, Guo J, Weisel RD, Li R-K. Repeated and transfer of sngiogenic plasmids into the infarcted rat heart via ultrasound targeted microbubble destruction enhances cardiac repair. European Heart Journal. 2011:32(16):2075-94.

• Huang X-P, Sun Z, Miyagi Y, McDonald Kinkaid HY, Zhang L, Weisel RD, Li R-K. Differentiation of allogeneic mesenchymal stem cells induces immunogenicity and limits their long-term benefits for myocardial repair. Circulation. 2010 Dec;122(23):2419-29.

• Miyagi Y, Zeng F, Huang XP, Foltz WD, Wu J, Mihic A, Yau TM, Weisel RD, Li R-K. Surgical ventricular restoration with a cell- and cytokine-seeded biodegradable scaffold. Biomaterials. 2010 Oct;31(30):7684-94.

• Sun Z, Zhang Y, Brunt KR, Wu J, Li SH, Fazel S, Weisel RD, Keating A, Li R-K. An adult uterine hemangioblast: evidence for extramedullary self-renewal and clonal bilineage potential. Blood. 2010 Oct;116(16):2932-41.

• Xaymardan M, Cimini M, Fazel S, Weisel RD, Lu W-Y, Martin U, Harvey RP, Li R-K. c-kit function is necessary for in vitro myogenic differentiation of bone marrow hematopoietic cells. Stem Cells. 2009 Aug;27(8):1911-20.

• Fujii H, Sun Z, Li S-H, Wu J, Fazel S, Weisel RD, Rakowski H, Linder J, Li R-K. Ultrasound-targeted gene delivery induces angiogenesis after a myocardial infarction in mice. Journal of the American College of Cardiology: Cardiovascular Imaging. 2009 Jul;2(7):869-79.

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