Cardiac Regeneration

Overview

Mammalian hearts do not have the capacity to regenerate, unlike hearts from certain fish and amphibians. So following a myocardial infarction, cells in the heart die, there is no mechanism for replacing these cells, and scar tissue is formed. We are investigating the possibility of replacing the dead heart cells using stem cells - these are cells that have the ability to divide into another cell type, and can be obtained from foetal or embryonic tissue, or adult bone marrow. However, the heart does have the capacity to form new blood vessels - the process of angiogenesis. So it is also possible to improve blood flow to an area of the heart that has been deprived of blood. Various growth factors can promote angiogenesis, and we are investigating methods of delivering these to the heart, as well as which combinations prove most effective. Studies focus on therapeutic angiogenesis and cardiac regeneration by gene and cell therapy.

Growth factors and angiogenesis

Nerve growth factor (NGF) induces reparative angiogenesis and prevents apoptosis in ischaemic and diabetic limb muscles. One area of study involves the potential of neurotrophin gene therapy of the infarcted heart of normoglycemic and diabetic mice to prevent maladaptative remodeling and heart failure.

We also aim to develop more effective strategies to treat chronic limb and myocardial ischaemia. Research also addresses diabetes-related microvascular complications, in particular impaired angiogenesis and wound healing. To achieve these aims, our group is applying state of the art concepts in the new field of therapeutic angiogenesis, which postulates that local delivery of growth factors that can promote clinically valuable increase in blood flow. Such growth factors are either delivered as proteins or as gene therapy.

This includes the identification of novel angiogenic factors, in particular human tissue kallikrein and nerve growth factor, and developing platforms for translational research to bring these discoveries from the bench to the bedside.

Stem cells

More recently, the idea has emerged that therapeutic angiogenesis can also be achieved using stem cell transplantation. We are currently engaged in studies aimed at challenging the therapeutic potentiality of human stem cells (embryonic, foetal, and adult) for the regeneration of wounded tissues in murine models of myocardial infarction and ischaemic diabetic wounds.

We are also studying the therapeutic potential of human foetal progenitor cells to repair the ischaemic heart. But stem cells can also be derived from a patient's own bone marrow, and by isolating and culturing the cells having the potential to form cardiac myocytes, we may be able to improve treatment patients with end-stage heart failure: By performing a left-ventricular reshaping operation on such hearts, their pumping efficacy can be improved. However, they contain much scar tissue. The stem cells can potentially replace the scar tissue (that is removed in the operation), and be used to rebuild the heart muscle. More information about the left-ventricular reshaping operation can be found here.

Microvascular Permeability

The primary function of the cardiovascular system is to deliver nutrients to cells, and remove metabolic wastes. Water and nutrients move from the blood to the tissue across the walls of capillaries and venules. The rate at which this happens depends on a number of factors, one of which is the permeability of the capillary wall.

During the process of angiogenesis, the new blood vessels appear to have a higher permeability than established vessels, and that a specific growth factor for endothelial cells (VEGF), also causes increased permeability. Development of highly permeable new microvessels is critically important in a number of very common, and potentially lethal diseases. Tumour formation, diabetes, psoriasis, atherosclerosis and arthritis are also associated with high permeability, and high VEGF production.

An understanding how permeability and angiogenesis are related, will hopefully lead to new strategies for drug design,and novel therapies for these conditions, as well as helping us to understand how our bodies function normally.

To find out more about this research please visit the Microvascular Research Laboratories homepage.