Impact of dual stem cell therapy on SDF1-CXCR4-axis, GLP-1 receptors and microRNA expression patterns after myocardial infarction.

• Applicant: Dr. Hans D. Theiss
• Subject Area: Cardiology, Angiology
• Term: from 2008 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 56870822

Many studies have demonstrated that transplantation or mobilisation of stem cells from bone marrow results in improved cardiac function and survival after myocardial infarction in animals. Probably, these effects are rather due to the paracrine potential of stem cells than to real transdifferentiation. However, clinical studies of stem cell therapy remained sobering: Some showed only moderate improvement of cardiac function and others were even negative. Keeping in mind the striking results of the animal studies, the promising approach of stem cell therapy after myocardial infarction obviously needs modifications and alternatives for clinical use. We believe that one important issue that definitively needs to be addressed is the complex of stem cell homing. This process mainly works through the interaction of myocardial SDF-1 with its receptor CXCR-4 that is expressed on stem cells. An upregulation of myocardial SDF-1 would improve stem cell homing considerably. Therefore, innovative strategies have to concentrate on increasing SDF-1 expression in the myocardium – as intended in the present application: We plan to analyse the effect of the administration of DPP-IV-inhibitors on stem cell homing, cardiac function and survival after myocardial infarction in a mouse model. Dipeptidyl peptidase IV (DPP-IV or CD26) degrades SDF-1 and can be inhibited by diprotin A. DPP-IV inhibitors like Vildagliptin or Sitagliptin are on the verge of clinical use in diabetes mellitus. In our study myocardial infarction is to be induced in mice by an established model of LAD-ligation. Thereafter, DPP-IV-inhibitors are administered in combination with or without G-CSF induced stem cell mobilisation. CD26-/- mice will serve as controls. Primary endpoints are survival and cardiac function as assessed by Kaplan-Meier curves and catheter-based Millar-tip analysis. Furthermore, the expression of myocardial homing factors (SDF-1 etc.) will be examined by quantitative RT-PCR and circulating stem cells by flow cytometry (FACS). Finally, it is intended to quantify stem cell homing in a transplantation model: EGFP-transgene bone marrow is transplanted in wild type mice; EGFP-positive stem cells can then be analysed by FACS after digestion of harvested hearts. In summary, our project will investigate the effects of pharmacological DPP-IV-inhibition after experimental myocardial infarction which might be a break-through in stem cell therapy.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Wolfgang-M. Franz