Electrical Stimulation of pediatric cardiac-derived c-kit+ progenitor cells improves retention and cardiac function in right ventricular heart failure

Abstract

Nearly 1 in every 120 children born has a congenital heart defect. Although surgical therapy has improved survival, many of these children go on to develop right ventricular heart failure (RVHF). The emergence of cardiovascular regenerative medicine as a potential therapeutic strategy for pediatric HF has provided new avenues for treatment with a focus on repairing or regenerating the diseased myocardium to restore cardiac function. Although primarily tried using adult cells and adult disease models, stem cell therapy is relatively untested in the pediatric population. Here, we investigate the ability of electrical stimulation (ES) to enhance the retention and therapeutic function of pediatric cardiac‐derived c‐kit+ progenitor cells (CPCs) in an animal model of RVHF. Human CPCs isolated from pediatric patients were exposed to chronic ES and implanted into the RV myocardium of rats. Cardiac function and cellular retention analysis showed electrically stimulated CPCs (ES‐CPCs) were retained in the heart at a significantly higher level and longer time than control CPCs and also significantly improved right ventricular functional parameters. ES also induced upregulation of extracellular matrix and adhesion genes and increased in vitro survival and adhesion of cells. Specifically, upregulation of β1 and β5 integrins contributed to the increased retention of ES‐CPCs. Lastly, we show that ES induces CPCs to release higher levels of pro‐reparative factors in vitro. These findings suggest that ES can be used to increase the retention, survival, and therapeutic effect of human c‐kit+ progenitor cells and can have implications on a variety of cell‐based therapies. Stem Cells 2019;37:1528–1541

Loss of cardiac myosin light chain kinase contributes to contractile dysfunction in right ventricular pressure overload

“…RV wall thickness during diastole (RVWT;d) was measured in the twodimensional short-axis view in M-mode. As previously shown, this surgery produces severe right ventricular dysfunction within two weeks post-banding (Maxwell et al, 2019;Trac et al, 2018). Right ventricular dysfunction was confirmed as at least a 40% reduction in TAPSE.…”

After the storm: an objective appraisal of the efficacy of c-kit+ cardiac progenitor cells in preclinical models of heart disease

“…These reports include at least 19 studies in mice, 23 in rats, seven in pigs, and one in cats; 12 of these studies were done in animal models of old MI (chronic ischemic heart failure), and seven were performed in large animal (swine) models (Table 1). Except for four studies in models of isoproterenol-induced cardiomyopathy (Taghavi et al 2015), right ventricular injury by pulmonary artery banding (Maxwell et al 2019;Wehman et al 2017), and transverse aortic constriction (Kazakov et al 2015), all of these studies consistently show that administration of CPCs improved cardiac function after an acute, subacute, or old MI, often in association with a reduction in scar size, which in aggregate provides robust preclinical evidence of efficacy (Table 1). One study (Ellison et al 2013) used both a model of acute MI and isoproterenol-induced cardiomyopathy.…”

“…In fact, a review of the literature demonstrates that there is extensive evidence from many other independent groups that administration of CPCs in preclinical models of ischemic cardiomyopathy (acute or old MI) is beneficial. As detailed in Table 1, at the time of this writing, at least 50 studies from 26 independent laboratories around the world have reported beneficial effects of CPCs in mice, rats, pigs, and cats (the 50 references are given in Table 1) (Alshammary et al 2013;Avolio et al 2015;Bao et al 2017;Bhutani et al 2018;Bolli et al 2013;Cai et al 2015;Carr et al 2011;Dergilev et al 2018;Duran et al 2013;Ellison et al 2013;Fischer et al 2009;Hong et al 2014;Kamata et al 2014;Karantalis et al 2015;Kazakov et al 2015;Kulandavelu et al 2016;Li et al 2017;Li et al 2011;Li et al 2012;Li et al 2018;Ma et al 2018aMa et al , 2018bMatsuda et al 2014;Maxwell et al 2019;Mohsin et al 2012;Natsumeda et al 2017;Oskouei et al 2012;Puddighinu et al 2018;Sharma et al 2015;Simpson et al 2012;Song et al 2016;Taghavi et al 2015;J.M. Tang et al 2015;X.L.…”

Double face of stem cells in paediatrics: therapeutic applications of mesenchymal stem cells and threats from cancer stem cells

“…There are also examples of the successful use of MSCs therapy in other areas of paediatrics, such as diabetes (9) , pulmonary and cardiac diseases (9,18,32,33) , reconstructive surgery and orthopaedy (9,34,35) , transplantation, and graft-versushost diseases (9,36) . One of the examples involves the successful treatment of diabetes mellitus in adolescents aged 14 to 22 years (9,37) with adipose-derived MSCs induced in vitro to produce insulin.…”