Servicenavigation

Project Details

Back

Projekt Print View

Elucidating the fate of CXCR4+ cell populations in the ischemic heart

Subject Area Cardiology, Angiology
Term from 2012 to 2017
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 213248637
 
Final Report Year 2017

Final Report Abstract

Stromal cell-derived factor-1 (SDF-1) and its corresponding receptor CXCR4 have been shown to play prominent roles during cardiovascular development, cardiac repair and tissue homeostasis after ischemia. In previous studies from our lab we could demonstrate that stabilization of SDF-1 by preventing its cleavage through inhibition of the protease CD26 increased recruitment of blood derived progenitor cells associated with attenuated post MI remodeling, improved myocardial function and increased survival in mice. However, SDF-1 mediated CXCR4+ cell recruitment and repair mechanisms are still barely understood. In the first aim of this proposal we characterized CXCR4+ cells and its subpopulations in BM and the ischemic heart ± prolyl hydroxylase (PH) inhibition using novel CXCR4-EGFP transgenic mice. BM and heart displayed increased numbers of CD45+/CXCR4- EGFP+/CD11b+ cell subsets after ischemia and PH treatment. Enhanced PH inhibition significantly upregulated reparative M2 like CXCR4-EGFP+ CD11b+/CD206+ cells compared to inflammatory CXCR4-EGFP+ CD11b+/CD86+ cells associated with reduced apoptotic cell death, increased neovascularization, reduced scar size and an improved heart function after MI. Our data suggest increased PH inhibition as a promising tool for a customized upregulation of SDF-1 and CXCR4 expression to attract reparative CXCR4+/CD11b+ cells to the ischemic heart associated with increased cardiac repair. This study received a best poster award at the European Society of Cardiology congress in London 2015. In the second aim, we were able to analyze the cell specific role of SDF-1 in cardiovascular development. We have produced a conditional smooth muscle cell specific SDF-1 knock-out mouse model and to our surprise we detected a severe hypertrophic cardiac phenotype with increased prenatal mortality of embryos. Surviving mice showed severe vascular defects, decreased cardiac output and stroke volumes associated with a severe hypertrophic phenotype. Further studies are underway to analyze cell signaling and transcriptome changes in KO animals. To further proceed with this very interesting new findings we have recently successfully applied for a research grant at the Austrian scientific fund. Finally, in the third aim we were not able to generate conditional CXCR4 (BAC)-CreERT2 lineage reporter mice to specifically fate map CXCR4+ expressing cells in the neonatal, adult and adult infarcted heart. However, recent developments in transcription activator-like effector nucleases (TALENs) and Clustered Regularly Interspaced Short Palindromic Repeats (Crisp/Cas) based systems have resulted in new transgenic techniques which do not have the drawbacks associated with BAC transgenesis. Therefore, we attempt to generate conditional CXCR4 (BAC)-CreERT2 reporter mice utilizing novel transgenic techniques in the future. In summary, we could identify PH inhibition as a promising tool for a customized upregulation of SDF-1 and CXCR4 expression to attract reparative CXCR4+/CD11b+ cells to the ischemic heart associated with increased cardiac repair. Moreover, we gained novel mechanistical insights in basic repair mechanisms mediated via the SDF-1/CXCR4 axis which might be leading to new regenerative therapies.

Publications

 
 

Additional Information

© 2024 DFG Disclaimer / Copyright / Privacy Policy

Textvergrößerung und Kontrastanpassung