Dr. Sanjiv Dhingra
Cardiac Regeneration and Tissue Engineering Laboratory, Institute of Cardiovascular Sciences
Regenerative Medicine Program, Department of Physiology, University of Manitoba
Dr. Dhingra’s laboratory focuses on various aspects of cardiac regeneration and myocardial tissue engineering using stem cell-based and biomaterials-based approaches to restore function following a cardiac injury. Clinical translation of stem cell based approaches depends upon in-depth knowledge of the donor stem cell and it is very important to develop a strong understanding of the survival pattern of donor cells following transplantation in the injured myocardium.
Dr. Dhingra’s immediate interests are to investigate the basic mechanisms of immune-rejection of transplanted allogeneic (unrelated donor) mesenchymal stem cells (MSCs), embryonic stem (ES) cells, induced pluripotent stem (iPS) cells in the heart in order to develop strategies to enhance the survival of these cells and successfully repair damaged myocardium. He is also interested in developing clinically relevant biomaterials for myocardial tissue engineering and developing the strategies to increase host immune tolerance to prevent the rejection of biodegradable patches and scaffolds seeded with stem cells and implanted into the injured heart.
Why is this work important?
Patient derived autologous stem cells have been demonstrated to be safe and effective for cardiac repair. In preclinical studies conducted in young animals, the transplanted MSCs significantly improved the cardiac function after acute or chronic myocardial infarction (MI). However, the initial clinical trials with autologous MSCs in ageing patients suggested only marginal beneficial effects on heart function. The difference between the preclinical and clinical trials was largely due to age-related decrease in the proliferation and regenerative capability of MSCs from aged patients compared to the healthy young animal donors. Unfortunately, the risk of congestive heart failure (CHF) rises with increasing age due to the malfunction of the angiogenic repair mechanisms and several other reasons. Thus, a source of highly regenerative donor stem cells would dramatically improve the ability of stem cell therapy to prevent CHF in older, debilitated patients. To this end, allogeneic stem cells isolated from healthy, young volunteers are good candidate cells for cardiac regeneration and repair. However, the long-term ability of allogeneic cell therapy to preserve heart function is limited because very few allogeneic cells escape the host immune response and survive in the myocardium. Various studies using different cell types have reported that the improvement in heart function was found to be proportional to the number of implanted cells surviving in the myocardium. Hence, the development of new strategies to suppress host immune responses and enhance the survival of transplanted allogeneic cells could have tremendous impact on the outcome of stem cell therapy for cardiac repair and regeneration.
What techniques and equipment are used in this laboratory?
This laboratory has techniques as well as tools to isolate and culture different stem cell populations and transplant these cells to the infarct area after inducing myocardial infarction in various animal models; combining stem cell biology and molecular biology techniques to accomplish research goals.
About Dr. Sanjiv Dhingra
Dr. Sanjiv Dhingra is an Assistant Professor in the Regenerative Medicine Program, Department of Physiology, University of Manitoba. Prior to joining as a faculty member in University of Manitoba, Dr. Dhingra received postdoctoral training in McEwen Centre for Regenerative Medicine, Toronto General Hospital and in the Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre in Winnipeg. He received postdoctoral fellowship awards from CIHR and MHRC with high rankings. In October 2007, Dr. Dhingra received an award from Life Science Association of Manitoba for his contribution to cardiovascular research. In May 2010 he received the Early Career Investigator Award from the International Society of Heart Research in Kyoto, Japan. Recently, Dr. Dhingra was a finalist for the Vivien Thomas Young Investigator Award at American Heart Association Scientific Sessions in Los Angeles. In addition to his research program, Dr. Dhingra is also responsible for directing the Canada Italy Tissue Engineering Laboratory (CITEL), a collaboration between the University of Rome “Tor Vergata” and the Institute of Cardiovascular Sciences, St. Boniface Research Centre. Under his supervision CITEL will develop innovative technologies for biomaterials and will define pioneering procedures for cardiac tissue engineering.
For more information, contact:
Dr. Sanjiv Dhingra
Tel. (204) 235-3454 (Office) (204) 235-3648 (Lab)
St-Boniface Hospital Research
R3028-2, 351 Taché Avenue,
Preventing the rejection of allogeneic stem cells
Allogeneic stem cells offer several advantages over autologous cells, including excellent regenerative potential, immediate availability for clinical application. In various pre-clinical and clinical studies allogeneic mesenchymal stromal cells (MSCs), embryonic stem (ES) cells or induced pluripotent stem (iPS) cells have been demonstrated to engraft in the infarcted heart, differentiate into different cell types of cardiac lineage and induce cardiac repair. However in all these studies the long-term fate of the cells in the recipient myocardium was not assessed. We recently observed that after implantation, differentiation of allogeneic mesenchymal stem cells within the infarcted myocardium results in the loss of their immunoprivilege and rejection of these cells by the heart and progressive deterioration of ventricular function. Also in various pre-clinical models allogeneic embryonic stem cells and iPS implanted into different disease models were recognized by recipient immune system and rejected. Thus, an in-depth investigation of the immune characteristics of allogeneic stem cells and their interaction with the recipient immune system seems necessary to prevent the rejection of transplanted allogeneic cells and to improve their efficacy for cardiac repair.
My research program investigates the effect of stem cell differentiation on their immunogenicity. We use pharmacological and genetic interventions to study the molecular mechanisms responsible for alterations that lead to changes in the immune characteristics of stem cells following differentiation. This will help us in designing the strategies to preserve immunoprivilege of allogeneic stem cells. I believe that the benefit of current stem cell therapy based approaches to restore ventricular function after an extensive MI would be greatly enhanced if the cells could be rendered immunoprivileged. The studies have suggested that immunosenescence is a barrier to transplant tolerance and the changes associated with the process of ageing create a barrier to tolerance for allograft. Thus another approach that I want to use to prevent rejection of allogeneic stem cells in the injured myocardium will be to increase the immune tolerance in aged recipients by targeting the cytotoxic T cell activation pathways, and by regulatory T cell induction. This will help in designing new therapies to promote immune tolerance and cell survival.
My laboratory also aims to develop clinically relevant and robust technologies to discover biomaterials for cardiac tissue engineering. Our long-term goals in this direction are to engineer tissue grafts for application in cardiac regenerative medicine. Biological scaffold materials currently being used for cardiac tissue engineering are made from different animal, tissue and cell sources, raising concerns about the effect of the immune response to biomaterials. Commonly used commercial products are derived from both allogeneic and xenogeneic sources and allo-immune responses by the recipients against these materials have not been investigated thoroughly. Basically the allogeneic and xenogeneic surface antigens and epitopes present in the biomaterials are thought to contribute to the host immune responses. Our focus is to develop an in-depth understanding of the host immune responses against biomaterials and the strategies to increase host immune tolerance to prevent the rejection of biodegradable patches and scaffolds implanted into the injured heart.
1. 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 (2013) Preserving PGE2 level prevents rejection of implanted allogeneic mesenchymal stem cells and restores post-infarction ventricular function. Circulation (in press).
2. Li P, Li SH, Wu J, Zang WF, Dhingra S, Weisel RD, Li R K (2013) Interleukin-6 downregulation with mesenchymal stem cells results in loss of immunoprivilege. J Cell Mol Med (in press).
3. Dhingra S, Huang XP, Li RK (2010) Allogeneic mesenchymal stem cells and cardiac repair. Trends Cardiovas Medicine 20; 263-268.
4. Guo J, Sun Z, Mihic A, Au S, Dhingra S, Wu J, Hatta K, Sun L, Zhang Y, Li SH, Huang XP Billio F, Weisel R, Li RK (2013) Novel Secreted CNPY2 binds VEGFR2 in Endothelial Cells and DSG1 in Smooth Muscle Cells to Promote Angiogenesis In Vitro and In Vivo. (in preparation).
5. Bagchi AK, Sharma AK, Dhingra S, Ludke ARL, Al-Shudiefat A, Singal PK (2013) Interleukin-10 activates Toll-like receptor 4 and requires MyD88 for cardiomyocyte survival. Cytokine 61; 304-14.
6. Al-Shudiefat AA, Sharma AK, Bagchi AK, Dhingra S, Singal PK (2013) Oleic Acid mitigates TNF-α induced oxidative stress in rat cardiomyocytes. Mol Cell Biochem 372; 75-82.
7. Dhingra S, Bagchi AK, Ludke AK, Sharma AK, Singal PK (2011) IL-10 modulation of TNF-α induced cardiomyocyte apoptosis is mediated by Akt via Stat3 activation. PLoS ONE 6(9):e25009.doi 10.371.
8. Ammar HI, Saba S, Ammar RI, Elsayed LA, Ghaly WBA, Dhingra S (2011) Erythropoietin protects against doxorubicin induced heart failure. Am J Physiol Heart Circ Physiol. 301 (6); H2413-21.
9. Khaper N, Bryan SA, Dhingra S, Singal R, Bajaj A, Pathak CM, Singal PK (2010) Targeting the Vicious Inflammation-Oxidative Stress Cycle for the Management of Heart Failure. Antioxidants and Redox Signaling. 13, 7, 1033-49.
10. Singh S, Dhingra S, Ramdath DD, Vasdev S, Gill V, Singal PK (2010) Risk factors preceding type 2 diabetes and cardiomyopathy. J of Cardiovasc Trans Res. 3, 580-596.
11. Dhingra S, Sharma AK, Arora RC, Slazek J, Singal PK (2009) IL-10 attenuates TNF-α induced NFκB pathway activation and cardiomyocyte apoptosis. Cardiovasc Res, April 1;82; 59-66.
12. Ludke A R L, Al-Shudiefat A A S, Dhingra S, Jassal D S, Singal P K (2009) Cardioprotective strategies in Doxorubicin-induced cardiotoxicity. Can J Physiol Pharmacol, 87;756-763.
13. Kaur K, Dhingra S, Sharma AK, Bajaj A, Singal PK (2009) Biology of TNFα and IL-10, and their imbalance in heart failure. Heart Fail Rev, 14: 113-123.
14. Dhingra S, Sharma AK, Singla DK, Singal PK (2007) p38 and ERK 1/2 MAPkinases mediate interplay of TNF-α and IL-10 in regulating oxidative stress and cardiac myocyte apoptosis. Am J Physiol Heart Circ Physiol 293; H3524-3531.
15. Sharma A K, Dhingra S, Khaper N & Singal P K (2007) Activation of apoptotic processes during transition from hypertrophy to heart failure in Guinea pigs Am J Physiol Heart Circ Physiol 293, H1384-90.
16. Singla DK, Kaur K, Sharma AK, Dhingra S, Singal PK (2007) Probucol Promotes Endogenous Antioxidant Reserve and Confers Protection against Reperfusion Injury. Can J Physiol Pharmacol 85; 439-43.
17. Kaur K, Sharma A K, Dhingra S, Singal P K (2006) Interplay of TNF-α and IL-10 in regulating oxidative stress in isolated adult cardiac myocytes. J Mol Cel Cardiol 41; 1023-1030.
18. Dhingra S & Bansal M P (2006) Hypercholesterolemia and LDL receptor gene expression: Modulation by selenium supplementation. Biometals 19; 493-501.
19. Dhingra S & Bansal M P (2006) Hypercholesterolemia and tissue specific differential mRNA expression of type-1 5´-iodothyronine deiodinase under different selenium status in rat. Biol Res 39, 307-319.
20. Dhingra S & Bansal M P (2006) Attenuation of LDL receptor gene expression by selenium deficiency during hypercholesterolemia. Mol Cell Biochem 282, 75-82.
21. Dhingra S & Bansal M P (2006) Modulation of hypercholesterolemia induced alterations in apolipoprotein B and HMG-CoA reductase expression by selenium supplementation. Chemico Biol Inter 161, 49-56.
22. Dhingra S & Bansal M P (2005) Hypercholesterolemia and apolipoprotein B expression: Regulation by Selenium status. Lipids in Health and Disease 4, 28.
23. Dhingra S, Singh U & Bansal M P (2004) Effect of selenium depletion and supplementation on the kinetics of type-I 5′-iodothyronine deiodinase and T3/T4 in rats. Bio Trace Ele Res 97, 95-104.
24. Dhingra S, Singh U & Bansal M P (2003) Protective role of selenium status on T3/T4 kinetics in rats under hyperlipidemia. Indian J Biochem Biophys 4, 260.
2012, Vivien Thomas Young Investigator Award (Finalist) (AHA Scientific Sessions, Los Angeles)
2011, Travel Award Winnipeg Heart International Conference, Winnipeg
2011, Stem Cell Network of Canada-Pfizer’s See the Potential Postdoctoral Fellowship Finalist in 2011competition
2011, Finalist, Young Investigator Award, Winnipeg Heart International Conference
2010, Early Career Investigator Award, ISHR, XXth World Heart Congress, Kyoto, Japan
2009, CIHR-RPP Postdoctoral Fellowship
2009, Best Oral Presentation Award, 5th Cardiac Sciences Resident Research Symposium,
2009, Travel Award, 1st Cuba-Canada International Heart Symposium, Holguin
2008, CIHR, Heart & Stroke Foundation-IMPACT Postdoctoral Fellowship
2008, Dr. Arnold Naimark, Young Investigator Award, Institute of Cardiovascular Sciences, University of Manitoba
2008, Junior Scientist Award in Physiology, Federation of American Societies for Experimental Biology, San Diego, USA
2007, Manitoba Health Research Council, Postdoctoral Fellowship (Application ranked 1 out of 24)
2007, Outstanding Contribution to Cardiovascular Research, Life Science Association of Manitoba
2006, Best Poster Presentation Award, International Symposium on Emerging Trends in Biochemistry, Chandigarh, India
2006,Travel Award, CSIR, 13th International Symposium on Atherosclerosis, Kyoto, Japan
2006, Best Poster Presentation Award, 13th International Symposium on Atherosclerosis, Kyoto, Japan
2005, Graduate Student Fellowship, ICMR, India
2003, Best Poster Presentation Award, National Symposium on Oxidative Stress, India
St. Boniface Hospital Foundation
Regenerative Medicine Program, Faculty of Medicine University of Manitoba
Vice President of Research University of Manitoba
Canada Italy Tissue Engineering Laboratory (CITEL)
CITEL is a translational research program which was established in 2013 by Dr. Grant Pierce at the St. Boniface Albrechtsen Research Centre. This is a unique collaboration with the University of Rome and Scuola Superiore in Pisa Italy. The Principal Investigators directing this program are Dr. Sanjiv Dhingra (St. Boniface Research Centre), Dr. Paolo Di Nardo (University of Rome) and Dr. Vincenzo Lionetti (Pisa, Italy). CITEL is committed to synthesis and application of novel stem cells and biomaterials based therapies for cardiac regeneration and repair. CITEL is also promoting exchange of students/postdocs/clinical fellows between St. Boniface Hospital Research Centre and University of Rome. In the past 5 years, two master’s students, Mr. Matteo Ciocci (in March 2015) and Ms. Sara Loconsolo (in March 2016) from the University of Rome, visited Dr. Sanjiv Dhingra’s laboratory at the Institute of Cardiovascular Sciences, St. Boniface Albrechtsen Research Centre. Under the banner of CITEL program, Dr. Dhingra and Dr. Di Nardo organized an international conference on the Future of Regenerative Medicine in Tuscania, Italy in October 2017. This meeting was attended by more than 70 scientists, clinicians and industry personnel to discuss clinically relevant issues related to regenerative medicine and tissue engineering. Through these collaborative efforts Dr. Di Nardo and Dr. Dhingra also edited a book entitled “Adult Stem Cells” published by Springer in the series “Methods in Molecular Biology”.