• 1.

    Parker HG, Kilroy-Glynn P. Myxomatous mitral valve disease in dogs: does size matter? J Vet Cardiol 2012;14:1929.

  • 2.

    Borgarelli M, Buchanan JW. Historical review, epidemiology and natural history of degenerative mitral valve disease. J Vet Cardiol 2012;14:93101.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Dillon AR, Dell’Italia LJ, Tillson M, et al. Left ventricular remodeling in preclinical experimental mitral regurgitation of dogs. J Vet Cardiol 2012;14:7392.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Boswood A, Haggstrom J, Gordon SG, et al. Effect of pimobendan in dogs with preclinical myxomatous mitral valve disease and cardiomegaly: the EPIC study-a randomized clinical trial. J Vet Intern Med 2016;30:17651779.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Uechi M. Mitral valve repair in dogs. J Vet Cardiol 2012;14:185192.

  • 6.

    Bartolucci J, Verdugo FJ, Gonzalez PL, et al. Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure: a phase 1/2 randomized controlled trial (RIMECARD trial [randomized clinical trial of intravenous infusion umbilical cord mesenchymal stem cells on cardiopathy]). Circ Res 2017;121:11921204.

    • Search Google Scholar
    • Export Citation
  • 7.

    Chugh AR, Beache GM, Loughran JH, et al. Administration of cardiac stem cells in patients with ischemic cardiomyopathy: the SCIPIO trial: surgical aspects and interim analysis of myocardial function and viability by magnetic resonance. Circulation 2012;126:S54S64.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Fan M, Huang Y, Chen Z, et al. Efficacy of mesenchymal stem cell therapy in systolic heart failure: a systematic review and meta-analysis. Stem Cell Res Ther 2019;10:150.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Perin EC, Willerson JT, Pepine CJ, et al. Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. JAMA 2012;307:17171726.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Sanina C, Hare JM. Mesenchymal stem cells as a biological drug for heart disease: where are we with cardiac cell-based therapy? Circ Res 2015;117:229233.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Schulman IH, Hare JM. Key developments in stem cell therapy in cardiology. Regen Med 2012;7:1724.

  • 12.

    Ksiazek K. A comprehensive review on mesenchymal stem cell growth and senescence. Rejuvenation Res 2009;12:105116.

  • 13.

    Yu H, Lu K, Zhu J, et al. Stem cell therapy for ischemic heart diseases. Br Med Bull 2017;121:135154.

  • 14.

    Mathiasen AB, Haack-Sorensen M, Jorgensen E, et al. Autotransplantation of mesenchymal stromal cells from bone-marrow to heart in patients with severe stable coronary artery disease and refractory angina–final 3-year follow-up. Int J Cardiol 2013;170:246251.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Mathiasen AB, Jørgensen E, Qayyum AA, et al. Rationale and design of the first randomized, double-blind, placebo-controlled trial of intramyocardial injection of autologous bone-marrow derived Mesenchymal Stromal Cells in chronic ischemic Heart Failure (MSC-HF Trial). Am Heart J 2012;164:285291.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Williams AR, Suncion VY, McCall F, et al. Durable scar size reduction due to allogeneic mesenchymal stem cell therapy regulates whole-chamber remodeling. J Am Heart Assoc 2013;2:e000140.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Fu H, Chen Q. Mesenchymal stem cell therapy for heart failure: a meta-analysis. Herz 2020;45:557563.

  • 18.

    Petchdee S, Sompeewong S. Intravenous administration of puppy deciduous teeth stem cells in degenerative valve disease. Vet World 2016;9:14291434.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Silva GV, Litovsky S, Assad JA, et al. Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation 2005;111:150156.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Quimby JM, Webb TL, Habenicht LM, et al. Safety and efficacy of intravenous infusion of allogeneic cryopreserved mesenchymal stem cells for treatment of chronic kidney disease in cats: results of three sequential pilot studies. Stem Cell Res Ther 2013;4:48.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Crain SK, Robinson SR, Thane KE, et al. Extracellular vesicles from Wharton's jelly mesenchymal stem cells suppress CD4 expressing T cells through transforming growth factor beta and adenosine signaling in a canine model. Stem Cells Dev 2019;28:212226.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    IBM SPSS statistics 25 core system user's guide. Armonk, NY: IBM Corp, 2017;1310.

  • 23.

    SAS/STAT 9.4 user's guide. Cary, NC: SAS Institute Inc, 2013.

  • 24.

    Levit RD, Landazuri N, Phelps EA, et al. Cellular encapsulation enhances cardiac repair. J Am Heart Assoc 2013;2:e000367.

  • 25.

    Menasché P. Stem cells in the management of advanced heart failure. Curr Opin Cardiol 2015;30:179185.

  • 26.

    Qiu G, Zheng G, Ge M, et al. Mesenchymal stem cell-derived extracellular vesicles affect disease outcomes via transfer of microRNAs. Stem Cell Res Ther 2018;9:320.

    • Crossref
    • Search Google Scholar
    • Export Citation

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Intravenous administration of allogeneic Wharton jelly–derived mesenchymal stem cells for treatment of dogs with congestive heart failure secondary to myxomatous mitral valve disease

Vicky K. Yang DVM, PhD1, Dawn M. Meola BS1, Airiel Davis BS1, Bruce Barton PhD1, and Andrew M. Hoffman DVM, DVSC1
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  • 1 From the Department of Clinical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536 (Yang, Meola, Davis, Hoffman); and Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA 01655 (Barton). Dr. Davis' present address is the Astellas Institute for Regenerative Medicine, Marlborough MA 01752. Dr. Hoffman's present address is the Office of the Dean, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.

Abstract

OBJECTIVE

To evaluate whether mesenchymal stem cells (MSCs) can be safely administered IV to dogs with congestive heart failure (CHF) secondary to myxomatous mitral valve disease (MMVD) to improve cardiac function and prolong survival time.

ANIMALS

10 client-owned dogs with CHF secondary to MMVD.

PROCEDURES

Dogs with an initial episode of CHF secondary to MMVD were enrolled in a double-blind, placebo-controlled clinical trial. Five dogs in the MSC group received allogeneic Wharton jelly–derived MSCs (2 X 106 cells/kg, IV), and 5 dogs in the placebo group received a 1% solution of autologous serum (IV) for 3 injections 3 weeks apart. Cell-release criteria included trilineage differentiation, expression of CD44 and CD90 and not CD34 and major histocompatability complex class II, normal karyotype, and absence of contamination by pathogenic microorganisms. Patients were followed for 6 months or until death or euthanasia. Echocardiographic data, ECG findings, serum cardiac biomarker concentrations, CBC, and serum biochemical analysis results were obtained prior to and 4 hours after the first injection and every 3 months after the final injection.

RESULTS

Lymphocyte and eosinophil counts decreased significantly 4 hours after injection, and monocytes decreased significantly only in dogs that received an MSC injection. No significant differences were seen in the echocardiographic variables, ECG results, serum cardiac biomarker concentrations, survival time, and time to first diuretic drug dosage escalation between the 2 groups.

CONCLUSIONS AND CLINICAL RELEVANCE

This study showed that MSCs can be easily collected from canine Wharton jelly as an allogeneic source of MSCs and can be safely delivered IV to dogs with CHF secondary to MMVD.

Contributor Notes

Address correspondence to Dr. Yang (vicky.yang@tufts.edu).