In this project, emphasis will be given to the functional integration of embryonic stem cell derived early cardiomyocytes. Our previous experiments demonstrated that these cells more efficiently integrate into the host tissue. In the course of this project we will extend this and study the interaction of different cells during co-injection. It is also important to discriminate various degrees of cell damage in the host tissue and the consequences for cell integration (Fig. 1). We will also investigate the mechanisms of immunological responses and tolerance.
In this project, adult mice will be used. In sum 200-250 animals will be used in all experiments. The functional integration and maturation of different donor cells will be investigated at different developmental stages of the recipient mice (day 2, 6, 15 and >25). For each developmental stage and for each type of CSC 20-25 animals are needed.
Small infarction (ejection fraction 40-60%): Mechanisms of remodelling using adult and cord blood stem cells. Stabilisation of the infarction zone, vascularisation, determination of the microenvironment, matrix conditions etc. Improvement of diastolic relaxation (see Fig. 1).
Large infarction (ejection fraction less than 40%): Heart failure: new embryonic stem cell derived cardiomyocytes for replacement therapy of contractile elements (see Fig. 1).
Stem cell immunology: The mechanisms of reprogramming and transdifferentiation for establishment of cells resistant to host rejection will be investigated. Stem cell tracking (loading of stem cells with nanoparticles) will be performed for high resolution in vivo imaging.
Electrophysiological approaches (intracellular recordings with sharp microelectrodes, micro electrode array (MEA)) will be applied to in vivo resembling in vitro heart slices of 150µm to evaluate the quality and quantity of engraftment of different celltypes transplanted into cryoinfarcted hearts. Recordings will be performed at different time points after infarction to determine functional integration.
The coronary heart disease leads to myocardial infarction. Depending on the degree of impairment of the ejection fraction (EF) different strategies for cardiac repairment are envisaged.