Repeated doses of cardiac mesenchymal cells are therapeutically superior to a single dose in mice with old myocardial infarction

Abstract

We have recently demonstrated that repeated administrations of c-kitPOS cardiac progenitor cells (CPCs) have cumulative beneficial effects in rats with old myocardial infarction (MI), resulting in markedly greater improvement in left ventricular (LV) function compared with a single administration. To determine whether this paradigm applies to other species and cell types, mice with a 3-week- old MI received one or three doses of cardiac mesenchymal cells (CMCs), a novel cell type that we have recently described. CMCs or vehicle were infused percutaneously into the LV cavity, 14 days apart. Compared with vehicle-treated mice, the single-dose group exhibited improved LV ejection fraction (EF) after the 1st infusion (consisting of CMCs) but not after the 2nd and 3rd (vehicle). In contrast, in the multiple-dose group, LV EF improved after each CMC infusion, so that at the end of the study, LV EF averaged 35.5 ± 0.7% vs 32.7 ± 0.6% in the single-dose group (P < 0.05). The multiple-dose group also exhibited less collagen in the non-infarcted region vs the single-dose group. Engraftment and differentiation of CMCs were negligible in both groups, indicating paracrine effects. These results demonstrate that, in mice with ischemic cardiomyopathy, the beneficial effects of three doses of CMCs are significantly greater than those of one dose, supporting the concept that multiple treatments are necessary to properly evaluate the full therapeutic potential of cell therapy. Thus, the repeated-treatment paradigm is not limited to c-kit POS CPCs or to rats, but applies to other cell types and species. The generalizability of this concept dramatically augments its significance.

Repeated Administrations of Cardiac Progenitor Cells Are Superior to a Single Administration of an Equivalent Cumulative Dose

“…As expected,3, 4 the vehicle‐treated (control) group continued to show progressive deterioration of both regional and global LV function (Figure 2B through 2I). Thus, left ventricular ejection fraction, infarcted wall thickness in diastole and in systole, infarcted wall thickening fraction, and stroke volume decreased progressively, whereas LV EDV and ESV increased progressively compared with pretreatment values (at 30 days after MI) (Figure 2B through 2I).…”

“…Administration of cells is more efficacious when it is repeated 3, 4. However, subjecting patients to multiple cardiac catheterizations entails additional risks, costs, and logistical challenges that could be avoided if the same results could be achieved with 1 larger dose of cells.…”

“…However, it remains possible that a similar effect could be achieved simply by increasing the number of cells administered in 1 injection. Since in our previous studies3, 4 the total amount of transplanted cells in the multiple‐dose group was 3 times greater than in the single‐dose group, it is not clear whether the observed therapeutic superiority was caused by the greater total number of cells given or by the use of repeated injections. This issue has major clinical implications because repeated cell administrations in patients (either by the intracoronary or the intramyocardial route) pose significant challenges in terms of safety, cost, and practicality—challenges that could be obviated if the greater efficacy of multiple doses can be achieved by using 1 equivalent large dose.…”

Of mice and men: models and mechanisms of diabetic cardiomyopathy

“…These mice exhibit increased vascular density and decreased cardiomyocyte apoptosis compared to wild-type controls, which is paralleled by increased recruitment of c-kit + progenitor cells and their incorporation into the vasculature [20]. Repeated percutaneous infusions of cardiac mesenchymal cells in mice with ischemic cardiomyopathy significantly improve contractile function compared to a single dose treatment, which suggests that multiple infusions are required for the full therapeutic potential of cell therapy [86]. In STZ-induced T1D rats, treatment with the crosslink breaker ALT-711 decreases cardiac AGE levels, restores collagen solubility, and diminishes diabetes-induced gene expression [37].…”

Repeated Cell Therapy

“…1,2,9,10 Consequently, our grouphaspursuedan alternative strategy: we have sought to overcome poor engraftment by administering repeated cell doses. 11,12 …”