Cardiac regeneration is an ambitious field that aims to restore heart function by replacing the damaged heart muscle cells. This will eventually lead to replacement of the scar with new functioning heart muscle cells. In experimental studies, this has been achieved (to varying degrees of success) with various types of adult stem cells, and one part of this process is to alter the scar properties, and eventually degrade the scar, to allow new muscle to be formed. The most successful cell type at growing new muscle (skeletal myoblasts) failed in clinical trials because the new muscle cells were surrounded by the scar tissue (called extracellular matrix - ECM) and therefore did not connect with the host muscle cells. This resulted in life threatening rhythm disturbances. We do not know how scar tissue can resorb itself to allow the proliferation of muscle cells. This lack of knowledge is compounded by the lack of an experimental model to study.
We propose to develop a new model of scar tissue for ex-vivo experiments. From mice that have had a heart attack, we will remove the cardiac scar tissue and study it in the laboratory in an experimental setup. This grant will fund the development of the model.
1. Define and optimize the culture medium for the scar tissue and the mechanical tension under which the heart normally functions.
2. Assess the effects of various substances that are known to affect scar tissue on this model (examples include angiotensin II, TGFbeta, matrix metalloproteinases and others).
This grant will fund the organ bath for the mechanical tensioner, experimental procedures, protein and RNA studies, and histological evaluation of scar integrity. This will be replicated at multiple time-points using different media. The results of this series of experiments will set the stage for future studies to test the effects of adult stem cells on the scar and test agents to administer with the cells in order to enhance their ability to replace the scar. The ultimate goal is to improve therapies for patients suffering postinfarction heart failure.