Repairing a Damaged Heart
Ischemic heart disease remains the leading cause of death in Canada and worldwide. Modern medical management has improved the prognosis of patients after a myocardial infarction (MI), commonly known as a heart attack, but existing therapies are largely aimed at slowing disease progression rather than restoring lost contractile function. Transplantation of cardiomyocytes (heart muscle cells) produced from human pluripotent stem cells (hPSCs) offers a potential new therapy that could, for the first time, remuscularize and repair the heart.
Our Discoveries
- Identified methods to guide hPSCs to differentiate to heart muscle cells (cardiomyocytes).
- Generated pure populations of specialized types of human heart cells, including atrial, ventricular and pacemaker cells.
- Demonstrated that hPSC-derived cardiomyocytes can regenerate heart muscle in preclinical models of heart disease.
- Establish scalable methods for manufacturing mature hPSC-derived ventricular cells and demonstrated that these more mature cells yield better outcomes than their immature counterparts after transplantation.
Our Research
Drs. Gordon Keller and Michael Laflamme's laboratories are collaborating on the development of novel therapies for post-MI heart failure based on the transplantation of cardiomyocytes into the damaged area of the heart. Our goal is to restore the electrical and contractile function of injured hearts by generating new muscle in the scarred (damaged) area with hPSC-derived cardiomyocytes.
Their laboratories have already made a number of important advances in this area, including the development of efficient protocols to guide hPSCs to generate specialized cardiac subtypes, proof-of-concept transplantation studies with hPSC-derived cardiomyocytes in rodent MI models, and the first direct demonstration that hPSC-derived cardiomyocytes can become electrically integrated and beat synchronously with the host heart tissue. Our ongoing work builds on these successes to advance the development of a viable cell therapy for heart disease.
Current projects in the labs include:
- Developing methods to more efficiently produce the specific type of cardiomyocyte that is damaged following a heart attack.
- Developing approaches to produce more mature cardiomyocytes for transplantation.
- Developing methods to produce other cell types found in the heart from hPSCs and test if they improve (enhance) regeneration and repair of the heart when transplanted together with cardiomyocytes.
- Creating and validating new tools to study and characterize the electrical behaviour of hPSC-derived cardiac tissue grafts in the damaged heart.
- Exploring novel approaches to improve electromechanical integration of new the heart tissue that develops from the transplanted cells with the surround undamaged tissue of the host heart.
- Testing the ability of the hPSC-derived tissue to improve heart function in highly relevant preclinical MI models that most closely recapitulate human heart disease.
- Testing the safety of hPSC-derived cardiomyocyte transplantation in the same relevant preclinical MI models.
Eliminating Pacemakers
The heartbeat is initiated and regulated by specialized group of cardiomyocytes known as pacemaker cells. Failure of these pacemakers due to either age or disease can result in life threatening irregular or slow heart rhythm. The current treatment option for these conditions is the implantation of an electronic pacemaker device that takes over control of activating the heartbeat. Although effective, these devices have a number of disadvantages including the need for periodic battery replacement, a risk of lead infections, a lack of communication with the autonomous nervous system and a lack of adaption to growth in paediatric patients. Transplantation of pluripotent stem cell-derived pacemaker cells could overcome these disadvantages and present an attractive future therapy for patients with pacemaker dysfunction.
Our Discoveries
- Methods to direct the differentiation of hPSCs to make primary pacemaker cells.
- Methods to generate and isolate highly enriched populations of these pacemaker cells.
- Proof of concept studies in small, pre-clinical laboratory models demonstrating that these pacemaker cells can function as biological pacemaker and pace the heart.
Our Research
Dr. Stephanie Protze's lab is using developmental biology-based approaches to establish strategies to guide the differentiation of hPSCs into the two different types of pacemaker cells found in the heart. One goal of these studies is to generate 'biological pacemakers' from these cells that can be transplanted into patients with pacemaker dysfunction. A second goal of Dr. Protze's work is to use these hPSC-derived pacemaker cells to study specific diseases that affect pacemaker function, such as congenital heart block. These studies are carried out in the Petri dish and are aimed at identifying the causes of such diseases and ultimately identifying potential drugs to treat them.
Current projects include:
- Developing methods to generate atrioventricular node pacemaker cells from hPSCs.
- Establishing new in vitro models for conduction system diseases including congenital heart block and inappropriate sinus tachycardia.
- Implementing synthetic biology to enhance the function of stem cell-derived cardiomyocytes.
- Developing new 3D models to study human heart development and congenital heart diseases.
