Abstract
There is no effective treatment for the total recovery of myocardial injury caused by an anticancer drug, doxorubicin (Dox). In this study, using a Dox-induced cardiac injury model, we compared the cardioprotective effects of ventricular cells harvested from 11.5-day old embryonic mice (E11.5) with those from E14.5 embryos. Our results indicate that tail-vein-infused E11.5 ventricular cells are more efficient at homing into the injured adult myocardium, and are more angiogenic, than E14.5 ventricular cells. In addition, E11.5 cells were shown to mitigate the cardiomyopathic effects of Dox. In vitro, E11.5 ventricular cells were more migratory than E14.5 cells, and RT-qPCR analysis revealed that they express significantly higher levels of cytokine receptors Fgfr1, Fgfr2, Pdgfra, Pdgfrb and Kit. Remarkably, mRNA levels for Fgf1, Fgf2, Pdgfa and Pdgfb were also found to be elevated in the Dox-injured adult heart, as were the FGF1 and PDGFB protein levels. Addition of exogenous FGF1 or PDGFB was able to enhance E11.5 ventricular cell migration in vitro, and, whereas their neutralizing antibodies decreased cell migration. These results indicate that therapies raising the levels of FGF1 and PDGFB receptors in donor cells and or corresponding ligands in an injured heart could improve the efficacy of cell-based interventions for myocardial repair.
Highlights
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Some changes in heart rate, RR interval, PR interval and QTc were evident in the Dox-treated groups with or without cell injections compared to the saline treated group (Figure 7B,C,E,F), these changes were not significant. These results suggest that tail vein infusion of E11.5 ventricular cells was able to normalize the deleterious QRS changes associated with Dox-induced cardiac injury. 13 of 22
We previously showed that direct intracardiac injection of E11.5 ventricular cells can form larger grafts when compared to E14.5 ventricular cells due to developmental differences in the relative distribution of cardiac progenitor cells (CPCs) and CMs and their cell cycle activities [21]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Anticancer drugs such as doxorubicin (Dox), tyrosine kinase inhibitors and various immunotherapies are known to increase disease-free survival rates in the affected patients. Many of these therapies are associated with cardiotoxicity which makes it challenging for early detection and management of adverse cardiovascular complications in surviving patients [1,2]. In contrast to other cancer therapeutics, Dox is well known to induce apoptosis in the heart and other tissues by inhibiting the actions of Topoisomerase
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