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Comparison of One and Three Intraventricular Injections of Cardiac Progenitor Cells in a Murine Model of Chronic Ischemic Cardiomyopathy

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Abstract

Repeated doses of c-kit+ cardiac progenitor cells (CPCs) are superior to a single dose in improving LV function in rats with old myocardial infarction (MI). However, this concept needs testing in different species to determine whether it is generalizable. We used a new murine model of chronic ischemic cardiomyopathy whose unique feature is that cell therapy was started late (3 months) after MI. Mice received three echo-guided intraventricular infusions, 5 weeks apart, of vehicle, CPCs × 1, or CPCs × 3. Echocardiography demonstrated that the single-dose group exhibited improved LV ejection fraction (EF) after the 1st infusion (CPCs), but not after the 2nd and 3rd (vehicle). In contrast, in the multiple-dose group LVEF continued to improve, so that the final value was greater than in vehicle or single-dose groups (P < 0.05). Hemodynamic studies showed that compared with vehicle, both preload-dependent and preload-independent functional parameters were significantly increased in the multiple-dose group but not in the single-dose group. Thus, two independent methods of functional assessment (echocardiography and hemodynamic studies) consistently demonstrated the superiority of three doses of CPCs vs. one dose. Compared with the single-dose group, the multiple-dose group exhibited less LV hypertrophy, as evidenced by a greater reduction in LV/body weight ratio and cardiomyocyte cross-sectional area. Furthermore, unlike the single dose, three CPC doses reduced myocardial inflammatory cells in the risk region. This is the first study of echo-guided intraventricular infusion of CPCs in mice with chronic ischemic cardiomyopathy. The results demonstrate that the beneficial effects of three CPC doses are greater than those of one dose, supporting the concept that multiple treatments are necessary to properly evaluate cell therapy. Our findings indicate that this concept applies not only to rat models but also to murine models. The generalizability of this strategy greatly enhances its importance and provides a rationale for large animal studies.

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Abbreviations

CPC:

Cardiac progenitor cell

CMC:

Cardiac mesenchymal cell

MI:

Myocardial infarction

LV:

Left ventricle

LVEDV:

End-diastolic LV volume

LVESV:

End-systolic LV volume

SV:

Stroke volume

EF:

Ejection fraction

PV:

Pressure–volume

WGA:

Wheat germ agglutinin

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Acknowledgements

This work was supported by National Institutes of Health grants P01 HL078825 and UM1 HL113530.

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Authors and Affiliations

  1. Division of Cardiovascular Medicine and Institute of Molecular Cardiology, University of Louisville, 550 S. Jackson St., ACB, 3rd Floor, Louisville, KY, 40292, USA

    Yiru Guo, Yibing Nong, Qianhong Li, Alex Tomlin, Arunpreet Kahlon, Anna Gumpert, Xiaoping Zhu & Roberto Bolli

  2. Institute for Heart Research, Bratislava, Slovakia

    Jan Slezak

Authors
  1. Yiru Guo
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  2. Yibing Nong
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  3. Qianhong Li
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  4. Alex Tomlin
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  5. Arunpreet Kahlon
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  6. Anna Gumpert
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  7. Jan Slezak
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  8. Xiaoping Zhu
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  9. Roberto Bolli
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Contributions

All authors meet the International Committee for Medical Journal Editors (ICMJE) authorship criteria. Y.G., Y.N., A.T., and R.B. analyzed and interpreted the data and drafted the manuscript. Y.G., Y.N., A.T., and X.Z. performed surgery, cell injections and acquisition of the data. Y.G., A.T., and X.Z. prepared the figures and tables. Q.L. provided CPCs and vehicle, as well as IdU, BrdU and minipumps for BrdU administration. A.G. performed pathology studies. Q.L., Y.G., A.K., J.S. and R.B. made substantial contributions to the design and critically revised the manuscript. All authors reviewed and approved the final version of the manuscript.

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Correspondence to Roberto Bolli.

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Guo, Y., Nong, Y., Li, Q. et al. Comparison of One and Three Intraventricular Injections of Cardiac Progenitor Cells in a Murine Model of Chronic Ischemic Cardiomyopathy. Stem Cell Rev and Rep 17, 604–615 (2021). https://doi.org/10.1007/s12015-020-10063-0

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