Een herdefiniëring van de interstitiële stamcel populaties in spierdystrofie

Muscular dystrophies (MDs) are chronic degenerative myopathies, whereof cardiac failure is still the most prominent cause of death. Cardiac cell therapies struggle with inefficient migration, engraftment and differentiation capacities of stem cells. We want to investigate whether epigenetic memory could be a tool to overcome these insufficiencies. We will derive canine cardiovascular progenitors (CPs) via factor-based- or direct reprogramming of isogenic skin fibroblast (SFs), cardiac fibroblasts (CFs) and cardiac mesoangioblasts (cMABs). We will ask whether the derived CPs express a bias towards cardiomyogenic differentiation or migration capacities. This will be examined by analysis of epigenetics, differentiation and migration. We will inject derived CPs in the systemic circulation of immunodeficient dystrophic mice to analyse migration and engraftment potential, and directly into the myocardium to analyse differentiation potential. As a proof of principle, we plan to inject golden retriever muscular dystrophy (GRMD) dogs by intra-coronary delivery and examine migration via multimodal imaging (MMI) and cardiac function by MRI/echocardiography. In summary, we will explore whether the epigenetic memory is a potential mechanism to boost cardiomyogenic and migration capacities of stem cells. In addition, this project can potentially contribute to refine cardiac cell therapies for not only MDs, but also in the broader context of cardiac failure.

Jaar van publicatie:2019