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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.

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Acknowledgements

This work was supported by NIH Grants P20 GM103492, P01 HL078825 (to RB and MW), and UM1 HL113530 (to RB), and an AHA Scientist Development Grant 13SDG14560005 (to MW).

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Correspondence to Roberto Bolli.

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395_2017_606_MOESM1_ESM.pptx

Supplementary Fig. 1. CMC cytokine profile. A Proteome Profiler™ Mouse XL Cytokine Array was used to evaluate the secretome of CMCs. Conditioned media from three independent isolations were combined to perform the assay

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Guo, Y., Wysoczynski, M., Nong, Y. et al. Repeated doses of cardiac mesenchymal cells are therapeutically superior to a single dose in mice with old myocardial infarction. Basic Res Cardiol 112, 18 (2017). https://doi.org/10.1007/s00395-017-0606-5

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  • DOI: https://doi.org/10.1007/s00395-017-0606-5

Keywords

  • Ischemic cardiomyopathy
  • Stem cells
  • Progenitor cells
  • Cell therapy