Targeting chronic cardiac remodeling with cardiac progenitor cells in a murine model of ischemia/reperfusion injury

Abstract

BackgroundTranslational failure for cardiovascular disease is a substantial problem involving both high research costs and an ongoing lack of novel treatment modalities. Despite the progress already made, cell therapy for chronic heart failure in the clinical setting is still hampered by poor translation. We used a murine model of chronic ischemia/reperfusion injury to examine the effect of minimally invasive application of cardiac progenitor cells (CPC) in cardiac remodeling and to improve clinical translation.Methods28 days after the induction of I/R injury, mice were randomized to receive either CPC (0.5 million) or vehicle by echo-guided intra-myocardial injection. To determine retention, CPC were localized in vivo by bioluminescence imaging (BLI) two days after injection. Cardiac function was assessed by 3D echocardiography and speckle tracking analysis to quantify left ventricular geometry and regional myocardial deformation.ResultsBLI demonstrated successful injection of CPC (18/23), which were mainly located along the needle track in the anterior/septal wall. Although CPC treatment did not result in overall restoration of cardiac function, a relative preservation of the left ventricular end-diastolic volume was observed at 4 weeks follow-up compared to vehicle control (+5.3 ± 2.1 μl vs. +10.8 ± 1.5 μl). This difference was reflected in an increased strain rate (+16%) in CPC treated mice.ConclusionsCPC transplantation can be adequately studied in chronic cardiac remodeling using this study set-up and by that provide a translatable murine model facilitating advances in research for new therapeutic approaches to ultimately improve therapy for chronic heart failure.

Anti-fibrotic Effects of Cardiac Progenitor Cells in a 3D-Model of Human Cardiac Fibrosis

“…Recently, we also observed that CPC injection could preserve end-diastolic dimensions post-MI in mice. Moreover, we noticed that measurements of regional wall motion parameters by speckle tracking analysis could reveal early changes in matrix remodeling upon CPC injection (17). The anti-fibrotic effects of CPCs seem to be paracrine in nature and seem to be mediated through exosomes, microRNAs, and endoglin (18, 19).…”

Trop2 Guarantees Cardioprotective Effects of Cortical Bone-Derived Stem Cells on Myocardial Ischemia/Reperfusion Injury

“…The emergence of stem cell therapy has provided an encouraging solutions for myocardial I/R injury 11 , 12 . Since the first experimental application of stem cells in diseased hearts, numerous studies have shown the therapeutic potential of transplantation of autologous cardiac stem cells, bone marrow-derived stem cells, induced pluripotent stem cell and endogenous progenitor cells in improving cardiac function after injury 13 – 17 . Although the safety and efficacy of these stem/progenitor cells in clinical trials have been demonstrated, overall functional improvements are limited.…”

Echocardiography-guided percutaneous left ventricular intracavitary injection as a cell delivery approach in infarcted mice

“…Both of these cell delivery approaches require a thoracotomy, which limits their applicability in studies requiring repeated cells administrations. Some researchers have proposed to use ultrasound-guided intramyocardial[11-14] or intrapericardial injection[33] to deliver therapeutic agents including cells. But in animal models of infarction, the pericardium is not intact and it is uncertain whether the injection needle can be kept in the pericardial space without stabbing the myocardium in a beating heart.…”

“…Finally, it is difficult to be certain that the injection needle remains inside the targeted myocardium during the entire injection without entering the LV cavity. These issues could be the reason why cells delivered via echo-guided intramyocardial injection did not yield cardiac functional improvement[11]. On the other hand, echo-guided LV intracavitary injection allows a larger injectable volume and a larger safe zone without penetrating into the myocardium.…”

“…Most cell delivery methods used in rodents require open-chest surgery[6-10], and in general, rodents do not tolerate multiple (>2) thoracotomies. Although ultrasound-guided transthoracic intramyocardial injection is a less invasive approach, the efficacy of this method in improving cardiac function remains unclear [11-14]. The uncertainty as to whether the needle tip remains inside the myocardium during the entire injection time (intermittent tip movements would result in cells being delivered into the pericardial space or the LV cavity), the limited targetable myocardial region, and the very limited injectable volume are major challenges that may prevent ultrasound-guided intramyocardial injection from being widely utilized for cell administration.…”