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

  • Yiru Guo
  • Marcin Wysoczynski
  • Yibing Nong
  • Alex Tomlin
  • Xiaoping Zhu
  • Anna M. Gumpert
  • Marjan Nasr
  • Senthikumar Muthusamy
  • Hong Li
  • Michael Book
  • Abdur Khan
  • Kyung U. Hong
  • Qianhong Li
  • Roberto Bolli
Original Contribution

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.

Keywords

Ischemic cardiomyopathy Stem cells Progenitor cells Cell therapy 

Notes

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).

Supplementary material

395_2017_606_MOESM1_ESM.pptx (521 kb)
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
395_2017_606_MOESM2_ESM.docx (19 kb)
Supplementary material 2 (DOCX 18 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Yiru Guo
    • 1
  • Marcin Wysoczynski
    • 1
  • Yibing Nong
    • 1
  • Alex Tomlin
    • 1
  • Xiaoping Zhu
    • 1
  • Anna M. Gumpert
    • 1
  • Marjan Nasr
    • 1
  • Senthikumar Muthusamy
    • 1
  • Hong Li
    • 1
  • Michael Book
    • 1
  • Abdur Khan
    • 1
  • Kyung U. Hong
    • 1
  • Qianhong Li
    • 1
  • Roberto Bolli
    • 1
  1. 1.Institute of Molecular CardiologyUniversity of Louisville School of MedicineLouisvilleUSA

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