Labs and Groups
Stewart Lab
Stewart Lab
Team Leader
Duncan Stewart
Senior Scientist, Regenerative MedicineWhat We Do
The Stewart Lab is focused on translational research utilizing stem/progenitor cells (i.e. endothelial progenitor cells EPCs, mesenchymal stem cells [MSCs], induced pluripotent stem cells [iPSCs]) for the treatment of cardiopulmonary and vascular diseases, together with enhancement strategies to increase their regenerative activity and overcome the deleterious effects of aging and attendant cardiac risk factors.
Ongoing projects range from basic science discovery research on novel mechanisms of pulmonary hypertension and the role of exosomes in mediating the therapeutic effects of stems cells in vascular disease, to translational research including clinical trials on gene-enhanced progenitor cell therapy for acute myocardial infarction and immunomodulatory cell therapy for septic shock.
The role of endothelial factors, such as nitric oxide and angiopoietins, in vascular health and disease, as well as in angiogenesis and neovascularization, continues to be a central focus for our work.
Our work is supported by:
Canada Foundation for Innovation
Canadian Institutes of Health Research
Ontario Research Fund
Ongoing projects range from basic science discovery research on novel mechanisms of pulmonary hypertension and the role of exosomes in mediating the therapeutic effects of stems cells in vascular disease, to translational research including clinical trials on gene-enhanced progenitor cell therapy for acute myocardial infarction and immunomodulatory cell therapy for septic shock.
The role of endothelial factors, such as nitric oxide and angiopoietins, in vascular health and disease, as well as in angiogenesis and neovascularization, continues to be a central focus for our work.
Our work is supported by:
Canada Foundation for Innovation
Canadian Institutes of Health Research
Ontario Research Fund
Research Activities
Fundamental mechanisms of cardiovascular disease and repair
Molecular analyses of endothelial cells (ECs) and blood from patients with pulmonary arterial hypertension (PAH) are being used to identify novel biomarker and therapeutic targets for this lethal disease, for example our recent discovery that TPT-1 (TCTP) mediates growth-dysregulation of ECs in complex arterial remodeling (Circulation 2014). Analyses at the proteome level, mRNA and miRNA, will lead to further dissection of the molecular underpinnings of this disease, for example, our identification of circulating miR-26a as a biomarker for PAH (AJRCCM 2013). Multi-tiered profiling will be used to study stem cell differentiation and dysfunction, informing new approaches for “enhanced” cell therapy for cardiovascular diseases.
Innovative approaches to address critical limitations to effective cell therapies
The Stewart Lab is focusing on overcoming major limitations of current cell therapies, beyond the use of gene-enhancement strategies to “rejuvenate” autologous progenitor cells, which we have now applied in two clinical trials. Our goal is to overcome the effect of age and co-morbidities on the activity of a patient’s own stem cells, using strategies to overcome cell senescence and/or dysfunction. Lack of cell persistence often precludes stem cells acting directly to regenerate damaged tissue by transdifferentiation. A novel “cocooning” technology pioneered in our lab uses a combinatorial cell-matrix approach to envelope single stem cells with functionalized hydrogel “cocoons”, increasing cell survival and engraftment. This is being transferred to an “on chip” microfluidic platform suitable for scale up to support large-scale preclinical and, ultimately, clinical testing.
Impactful human trials of innovative regenerative therapies
We are also spearheading the translation of the most promising approaches into innovative, first-in-human clinical trials and propose to translate the innovative new technologies developed above into the “next generation” of cell therapy trials. We have launched the first enhanced progenitor cell therapy trial for post heart attack repair and been guiding the Cellular Immunotherapy for Septic Shock (CISS) trial from our initial discovery to a phase 1 study. In the near future, PHACeT-2 will utilize strategies to yield more efficient and durable cell transfection. Future cardiac and pulmonary trials will use novel cell products developed above; i.e., exosomes or combinatorial cell products reproducing a portable stem cell niche.
Molecular analyses of endothelial cells (ECs) and blood from patients with pulmonary arterial hypertension (PAH) are being used to identify novel biomarker and therapeutic targets for this lethal disease, for example our recent discovery that TPT-1 (TCTP) mediates growth-dysregulation of ECs in complex arterial remodeling (Circulation 2014). Analyses at the proteome level, mRNA and miRNA, will lead to further dissection of the molecular underpinnings of this disease, for example, our identification of circulating miR-26a as a biomarker for PAH (AJRCCM 2013). Multi-tiered profiling will be used to study stem cell differentiation and dysfunction, informing new approaches for “enhanced” cell therapy for cardiovascular diseases.
Innovative approaches to address critical limitations to effective cell therapies
The Stewart Lab is focusing on overcoming major limitations of current cell therapies, beyond the use of gene-enhancement strategies to “rejuvenate” autologous progenitor cells, which we have now applied in two clinical trials. Our goal is to overcome the effect of age and co-morbidities on the activity of a patient’s own stem cells, using strategies to overcome cell senescence and/or dysfunction. Lack of cell persistence often precludes stem cells acting directly to regenerate damaged tissue by transdifferentiation. A novel “cocooning” technology pioneered in our lab uses a combinatorial cell-matrix approach to envelope single stem cells with functionalized hydrogel “cocoons”, increasing cell survival and engraftment. This is being transferred to an “on chip” microfluidic platform suitable for scale up to support large-scale preclinical and, ultimately, clinical testing.
Impactful human trials of innovative regenerative therapies
We are also spearheading the translation of the most promising approaches into innovative, first-in-human clinical trials and propose to translate the innovative new technologies developed above into the “next generation” of cell therapy trials. We have launched the first enhanced progenitor cell therapy trial for post heart attack repair and been guiding the Cellular Immunotherapy for Septic Shock (CISS) trial from our initial discovery to a phase 1 study. In the near future, PHACeT-2 will utilize strategies to yield more efficient and durable cell transfection. Future cardiac and pulmonary trials will use novel cell products developed above; i.e., exosomes or combinatorial cell products reproducing a portable stem cell niche.
Selected Publications
Granton J, Langleben D, Kutryk MB, Camack N, Galipeau J, Courtman DW, Stewart DJ. Endothelial NO-synthase gene-enhanced progenitor cell therapy for pulmonary arterial hypertension: The PHACeT Trial. Circ Res. 2015 Sept 11;117(7):645-54.
Lavoie JR, Ormiston M, Perez-Iratxeta C, Courtman DW, Jiang B, Ferrer E, Caruso P, Southwood M, Foster WS, Morrell NW, Stewart DJ. Proteomic analysis implicates translationally controlled tumor protein as a novel mediator of occlusive vascular remodeling in pulmonary arterial hypertension. Circulation. 2014 May 27;129(21):2125-35.
Mei SHJ, Haitsma JJ, Dos Santos CC, Deng Y, Lai PFH, Slutsky AS, Liles WC, Stewart DJ. Mesenchymal Stem Cells Reduce Inflammation While Enhancing Bacterial Clearance and Improving Survival in Sepsis. Am J Respir Crit Care Med. 2010 Oct 15;182(8):1047-57.
Taljaard M, Ward MR, Kutryk MJ, Courtman DW, Camack NJ, Goodman SG, Parker TG, Dick AJ, Galipeau J, Stewart DJ. Rationale and Design of ENACT-AMI: The first Randomized Placebo-controlled Trial of Enhanced Progenitor Cell Therapy for Acute Myocardial Infarction. Am Heart J. 2010 Mar;159(3):354-60.
Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res. 2005 Mar 4;96(4):442-50.
Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ. Expression of endothelin-1 in lungs of patients with pulmonary hypertension. New Engl J Med. 328(24): 1732-1739, 1993.
Lavoie JR, Ormiston M, Perez-Iratxeta C, Courtman DW, Jiang B, Ferrer E, Caruso P, Southwood M, Foster WS, Morrell NW, Stewart DJ. Proteomic analysis implicates translationally controlled tumor protein as a novel mediator of occlusive vascular remodeling in pulmonary arterial hypertension. Circulation. 2014 May 27;129(21):2125-35.
Mei SHJ, Haitsma JJ, Dos Santos CC, Deng Y, Lai PFH, Slutsky AS, Liles WC, Stewart DJ. Mesenchymal Stem Cells Reduce Inflammation While Enhancing Bacterial Clearance and Improving Survival in Sepsis. Am J Respir Crit Care Med. 2010 Oct 15;182(8):1047-57.
Taljaard M, Ward MR, Kutryk MJ, Courtman DW, Camack NJ, Goodman SG, Parker TG, Dick AJ, Galipeau J, Stewart DJ. Rationale and Design of ENACT-AMI: The first Randomized Placebo-controlled Trial of Enhanced Progenitor Cell Therapy for Acute Myocardial Infarction. Am Heart J. 2010 Mar;159(3):354-60.
Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res. 2005 Mar 4;96(4):442-50.
Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ. Expression of endothelin-1 in lungs of patients with pulmonary hypertension. New Engl J Med. 328(24): 1732-1739, 1993.