Abstract
ABSTRACTIschemic heart failure is the leading cause of mortality worldwide. An early boost of intracardiac regenerative key mechanisms and angiogenetic niche signaling in cardiac mesenchymal stem cells (MSCs) could improve myocardial infarction (MI) healing. Epicardial erythropoietin (EPO; 300 U kg−1) was compared with intraperitoneal and intramyocardial EPO treatments after acute MI in rats (n=156). Real-time PCR and confocal microscopy revealed that epicardial EPO treatment enhanced levels of intracardiac regenerative key indicators (SDF-1, CXCR4, CD34, Bcl-2, cyclin D1, Cdc2 and MMP2), induced transforming growth factor β (TGF-β)/WNT signaling in intramyocardial MSC niches through the direct activation of AKT and upregulation of upstream signals FOS and Fzd7, and augmented intracardiac mesenchymal proliferation 24 h after MI. Cardiac catheterization and tissue analysis showed superior cardiac functions, beneficial remodeling and increased capillary density 6 weeks after MI. Concomitant fluorescence-activated cell sorting, co-cultures with neonatal cardiomyocytes, angiogenesis assays, ELISA, western blotting and RAMAN spectroscopy demonstrated that EPO could promote cardiomyogenic differentiation that was specific of tissue origin and enhance paracrine angiogenetic activity in cardiac CD45−CD44+DDR2+ MSCs. Epicardial EPO delivery might be the optimal route for efficient upregulation of regenerative key signals after acute MI. Early EPO-mediated stimulation of mesenchymal proliferation, synergistic angiogenesis with cardiac MSCs and direct induction of TGF-β/WNT signaling in intramyocardial cardiac MSCs could initiate an accelerated healing process that enhances cardiac recovery.
Highlights
Ischemic heart failure is the leading cause of death in the modern world
We show that epicardial EPO delivery could efficiently trigger early regenerative signaling and proliferation in the heart, induce direct transforming growth factor β (TGF-β)/WNT signaling in intramyocardial mesenchymal stem cells (MSCs) niches and enhance angiogenesis, preserving cardiac function after acute myocardial infarction (MI)
We demonstrate that epicardial EPO delivery induces early proliferation factors cyclin D1 and Cdc2, and significantly increases dynamic proliferation in the early postischemic cardiac mesenchyme that hosts EPO-responsive highly angiogenetic cardiac MSCs
Summary
Further insight into the cell-specific mechanisms in specific cardiac stem cell niches of the adult ischemic heart could help us to understand their key roles in triggering regenerative impulses, reverse remodeling and restoring pump function. We demonstrated that the cardiac CD45−CD44+DDR2+ MSC subtype could take part in the very early cascades of myocardial regeneration (Klopsch et al, 2017). We show that epicardial EPO delivery could efficiently trigger early regenerative signaling and proliferation in the heart, induce direct transforming growth factor β (TGF-β)/WNT signaling in intramyocardial MSC niches and enhance angiogenesis, preserving cardiac function after acute MI. We provide the first evidence for an angiogenetic synergism of EPO with paracrine factors from post-ischemic cardiac CD45−CD44+DDR2+ MSCs and have investigated EPO-promoted cardiomyogenic differentiation in these cardiac MSCs. In addition, we have analyzed the human relevance of our findings in translational experiments
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