Regenerative Therapies Laboratory

Past Lab Members

• Xue-Wei Guo
• Samir Hazra
• Varun Kapila
• Alexander Kulik
• Daniel McKee
• Jimmy Song
• Erik Suuronen
• Geeta Waghray
• Serena Wong

Coronary artery disease is the leading killer of Canadians. Therapies to regenerate the heart and blood vessels by using gene or protein therapy, or the patient's own adult stem cells have so far yielded minimal, if any, benefit in humans, despite success in animal models. This disappointing result may be due to the tissues of humans being more aged and diseased, yet how this ultimately affects organ recovery remains unverified with respect to cell therapy.

In our lab, we are exploring, in a variety of experimental models, whether this assertion is true, and we are examining how this occurs and can be circumvented. We are investigating the use of diet modification and tissue engineered materials to improve the condition of the host tissue, and to deliver and enhance the retention of transplanted cells in the diseased tissue.

Cell therapy for the regeneration of the heart muscle and its associated blood supply is being evaluated along with novel strategies to enhance the environment of transplanted cells in order to improve their therapeutic effect. We anticipate that by improving the regenerating environment and the number and function of transplanted cells, our novel tissue engineering strategies will eventually make humans more responsive to cell therapies. Indeed, our ultimate objective is to make this very promising form of treatment clinically effective while ensuring its safety.

Matrix and Cell-based Therapeutic Angiogenesis

Coronary artery disease is the most important killer of Canadians. Despite major advances in therapy, there are still a significant number of patients identified with the disease who die of it. This is because over the long term, current treatments are not 100 per cent effective. Current treatments for blocked coronary arteries include bypass surgery and balloon angioplasty or stenting. These methods do not cure the disease and often fail over time.

In recent years, an experimental treatment called "therapeutic angiogenesis" has emerged. This approach mimics the natural process of blood vessel formation that occurs during growth and development. It is a very promising treatment for heart disease. It appears that this approach works best if performed using a patient's own cells from the bone marrow or blood. Therapeutic angiogenesis using cells aims to recreate what each adult human underwent as a baby. New arteries will be produced around the heart to take over damaged ones.

In this project, Dr. Marc Ruel and Erik Suuronen lead a team investigating new ways to grow and deliver a special type of cell to the heart. The cells of interest, termed endothelial progenitor cells, have the potential to create new arteries and can be obtained from a simple blood test. New culture techniques are being used to grow and expand the number of these cells and ways of redelivering them into the damaged heart are being developed. To this and, various novel tissue-engineered substances will be used as a delivery vehicles. These injectable materials solidify when raised to body temperature, providing an optimal scaffold for these cells to be implanted into the damaged tissue.

This research also aims to examine how the matrix can improve the effects of cell therapy. This may include the ability of the matrix to enhance transplanted cell survival, engraftment and function. In addition, matrices may improve local healing effects and may increase the recruitment of the body’s own stem cells for repair. The use of different animal models will allow us to determine the mechanisms that may be responsible for improved heart function from the combined use of matrix and cells for blood vessel regeneration.

Clinical trials so far have indicated that cell therapy in patients, although beneficial, is still much less effective than demonstrated in animal research models. This is likely due to the tissues of humans being more aged and diseased, yet how this ultimately affects organ recovery remains largely unverified with respect to cell therapy. In this research, we will explore, in a variety of experimental models, whether this assertion is true and thoroughly examine how this occurs and can be circumvented. We will investigate the use of tissue engineered materials to improve the condition of the host tissue and to deliver and enhance the retention of transplanted cells in the diseased tissue. We anticipate that by improving the regenerating environment and the number and function of transplanted cells, our novel tissue engineering strategies will eventually make humans more responsive to cell therapies. Indeed, our ultimate objective is to make this very promising form of treatment clinically effective while ensuring its safety.

Today's treatments are "mechanical" and do not cure heart disease. The failure to create new arteries means that long term success is not achieved. Angiogenesis is not a mechanical, but rather a biologic, natural way to grow blood vessels. This process will re-supply the heart with oxygen and restore its function. It is part of the therapeutic future and a main area of innovation in ischemic heart disease.

Myocardial Infarct Cell Therapy

Cell therapy for post-infarction impaired heart function has become a promising novel therapy. Experimental studies in animals and recent clinical trials in humans have outlined the current limitations of cellular transplantation. These include poor cell survival, lack of cell engraftment, and poor differentiation. However, evidence in animals suggests that the use of a three-dimensional scaffold may help enhance cell therapy and engineer myocardial tissue by improving initial cell retention, survival, differentiation, and integration. To date, contractility has been demonstrated in vitro only in biological scaffolds prepared from decellularized organs or tissue, or in porous tissue obtained by the physical cross-linking of collagen fibers. However, the reported contractility is low.

This project proposes to develop an injectable collagen scaffold that contains specific differentiating factors in order to improve the growth and maintenance of cardiomyocytes. Stem and progenitor cells with the potential to form new heart muscle will be tested with these scaffold materials. Their ability to improve cardiac remodelling, healing and contractility will be tested in animal models of infarcted myocardium.

Cell-based Therapy for Hibernating Myocardium

Hibernating myocardium is commonly observed in patients with severe diffuse coronary artery disease. It is also well established that patients with dysfunctional but viable hibernating myocardium who do not undergo revascularization are at high risk for cardiac events. These patients represent the very population for whom cell-based angiogenesis therapies are currently destined. In addition, patients with the undesirable combination of hibernating myocardium, poor heart function, and poor vessels at the time of coronary artery bypass grafting have a high operative risk and poor long-term outcomes despite modern medical and surgical treatments.

The therapeutic angiogenesis approach mimics the natural process of blood vessel formation that occurs during growth and development. It is a very promising treatment for heart diseas. It appears that it will work best if performed using a patient's own cells from the bone marrow or blood. Cell-based therapeutic angiogenesis aims to recreate what each adult human underwent as a baby. New arteries will be produced around the heart to take over damaged ones.

In this project, we use new methods and materials to deliver a special type of cells into the heart. These cells have the potential to create new arteries, and we have developed ways of redelivering them into the ischemic heart. Using a model that mimics human heart disease, we will evaluate the effects of blood stem cells (delivered with and without biopolymer matrix intended to enhance cell viability and retention upon delivery) on myocardial perfusion, metabolism and function using positron emission tomography (PET) and echocardiography. These are clinically relevant diagnostic tools that will provide assessment of the performance of cells and biopolymer matrices in the damaged heart.

Molecular Function and Imaging Program

The Molecular Function and Imaging Program (MFI) is a multidisciplinary research initiative supported by a grant from the Heart & Stroke Foundation of Ontario. The Program has grown from about 15 trainees in 2006 to 35 graduate students, post-doctoral fellows and medical residents and fellows in 2009. 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 the group, the common thread is the unique molecular imaging capabilities of positron emission tomography (PET).