Elucidating the fate of CXCR4+ cell populations in the ischemic heart
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
- (2017) Prolyl-hydroxylase inhibition induces SDF-1 associated with increased CXCR4+/CD11b+ subpopulations and cardiac repair. Journal of molecular medicine (Berlin, Germany) 95 (8) 825–837
Ghadge, Santhosh Kumar; Messner, Moritz; van Pham, Thi; Doppelhammer, Maximilian; Petry, Andreas; Görlach, Agnes; Husse, Britta; Franz, Wolfgang-Michael; Zaruba, Marc-Michael
(See online at https://doi.org/10.1007/s00109-017-1543-3) - Cell Tracking of CXCR4+ cells in the ischemic heart utilizing a novel CXCR4 (BAC)-EGFP transgenic mouse model. ESC Congress 2012, Munich. Abstract No 87306. European Heart Journal (2012) (Abstract Supplement)
Zaruba MM, Doppelhammer M, Kuehlenthal S, Franz WM
- Fate Mapping of CXCR4+ Cells in the Ischemic Heart Utilizing a Novel CXCR4 (BAC)-EGFP Transgenic Mouse Model. American Heart Association. Scientific Sessions 2012, Los Angeles. Abstract No. 13363. Circulation. 2012; 126: A13363
Zaruba MM, Doppelhammer M, Kuehlenthal S, Franz WM
- Inhibition of Prolyl Hydroxylase as a Novel Therapeutic Target for Hif-Mediated Sdf-1 Activation and Stem Cell Homing in the Ischemic Heart. American Heart Association. Scientific Sessions 2013, Dallas. Abstract No. 16652. Circulation. 2013; 128: A16652
Ghadge S, Doppelhammer M, Pham T.V., Kühlenthal S, Franz W.M., Zaruba M.M.
- Tracking of SDF-1+ and CXCR4+ cells in the ischemic heart utilizing novel (BAC)-EGFP reporter mice. Eur Heart J (2013) 34 (suppl 1)
Zaruba MM, Ghadge S, Doppelhammer M, Kuehlenthal S, Franz WM
(See online at https://dx.doi.org/10.1093/eurheartj/eht308.P1468) - Inhibition of Prolyl Hydroxylase as therapeutic target for HIF-mediated SDF-1 activation and stem cell homing in the ischemic heart. Clin Res Cardiol 103, Suppl 1, April 2014
Ghadge S, Pham, T.V., Doppelhammer M., Franz W.M., Zaruba M.M.
(See online at https://doi.org/10.1007/s00392-014-1100-9) - Inhibition of Prolyl Hydroxylase Stimulates Hif-mediated Sdf-1 Expression and CXCR4+ Cell Recruitment for Myocardial Repair. American Heart Association. Scientific Sessions 2014, Chicago. Abstract No. 18569. Circulation. 2014; 130: Suppl 2 A18569
Ghadge S, Pham T.V., Messner M, Doppelhammer M, Franz W.M., Zaruba M.M.
- Abstract: P1349 ESC Congress London 2015. Prolyl hydroxylase inhibition induces SDF-1 and CXCR4 expression to increase CXCR4+ cell homing and myocardial repair. European Heart Journal (2015) 36 (Abstract Supplement), 198
S.K. Ghadge, T.V. Pham, M. Messner, M. Doppelhammer, B. Husse, W.M. Franz, M.M. Zaruba
- Abstract 18567 AHA Scientific Sessions 2016. Inhibition of Prolyl Hydroxylase to Enhance Sdf-1 Expression for Augmented Cxcr4+ Cell Recruitment and Cardiac Repair. Circulation, 2016:134:A18567
Santhosh Kumar Ghadge, Moritz Messner, Thi Van Pham, Maximilian Doppelhammer, Andreas Petry, Agnes Goerlach, Britta Husse, Wolfgang-Michael Franz and Marc-Michael Zaruba
- Abstract: P3537 ESC Congress Rom 2016. Prolyl hydroxylase inhibition to enhance SDF-1 and CXCR4 expression for increased CXCR4+ cell homing and myocardial repair. European Heart Journal (2016) 37 (Abstract Supplement), 702
S.K. Ghadge, T.V. Pham, M. Messner, M. Doppelhammer, B. Husse, W.M. Franz, M.M. Zaruba
(See online at https://doi.org/10.1093/eurheartj/ehw433)
