Priming with Ligands Secreted by Human Stromal Progenitor Cells Promotes Grafts of Cardiac Stem/Progenitor Cells After Myocardial Infarction

Authors

  • Yoshitaka Iso,

    1. Department of Medicine, Stem Cell Core and, Cardiovascular Research Institute, University of Vermont, Colchester, Vermont, USA
    2. Department of Medicine, Cardiovascular Research Institute, University of Vermont, Colchester, Vermont, USA
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  • Krithika S. Rao,

    1. Department of Medicine, Stem Cell Core and, Cardiovascular Research Institute, University of Vermont, Colchester, Vermont, USA
    2. Department of Medicine, Cardiovascular Research Institute, University of Vermont, Colchester, Vermont, USA
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  • Charla N. Poole,

    1. Department of Biochemistry, Physician/Scientist Program, Tulane University, New Orleans, Louisiana, USA
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  • A. K. M. Tarikuz Zaman,

    1. Department of Medicine, Cardiovascular Research Institute, University of Vermont, Colchester, Vermont, USA
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  • Ingrid Curril,

    1. Department of Medicine, Stem Cell Core and, Cardiovascular Research Institute, University of Vermont, Colchester, Vermont, USA
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  • Burton E. Sobel,

    1. Department of Medicine, Cardiovascular Research Institute, University of Vermont, Colchester, Vermont, USA
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  • Jan Kajstura,

    1. Department of Anesthesiology and, Brigham and Women's Hospital Harvard Medical School, Boston, Massachusetts, USA
    2. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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  • Piero Anversa,

    1. Department of Anesthesiology and, Brigham and Women's Hospital Harvard Medical School, Boston, Massachusetts, USA
    2. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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  • Jeffrey L. Spees

    Corresponding author
    1. Department of Medicine, Stem Cell Core and, Cardiovascular Research Institute, University of Vermont, Colchester, Vermont, USA
    2. Department of Medicine, Cardiovascular Research Institute, University of Vermont, Colchester, Vermont, USA
    • Correspondence: Jeffrey L. Spees, Ph.D., Department of Medicine, University of Vermont, 208 South Park Drive, Suite 2, Colchester, Vermont 05446, USA. Telephone: 1-802-656-0666; Fax: 1-802-656-8932; e-mail: Jeffrey.Spees@uvm.edu

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Abstract

Transplantation of culture-expanded adult stem/progenitor cells often results in poor cellular engraftment, survival, and migration into sites of tissue injury. Mesenchymal cells including fibroblasts and stromal cells secrete factors that protect injured tissues, promote tissue repair, and support many types of stem/progenitor cells in culture. We hypothesized that secreted factors in conditioned medium (CdM) from adult bone marrow-derived multipotent stromal cells (MSCs) could be used to prime adult cardiac stem/progenitor cells (CSCs/CPCs) and improve graft success after myocardial infarction (MI). Incubation of adult rat CPCs in CdM from human MSCs isolated by plastic adherence or by magnetic sorting against CD271 (a.k.a., p75 low-affinity nerve growth factor receptor; p75MSCs) induced phosphorylation of STAT3 and Akt in CPCs, supporting their proliferation under normoxic conditions and survival under hypoxic conditions (1% oxygen). Priming CSCs with 30× p75MSC CdM for 30 minutes prior to transplantation into subepicardial tissue 1 day after MI markedly increased engraftment compared with vehicle priming. Screening CdM with neutralizing/blocking antibodies identified connective tissue growth factor (CTGF) and Insulin as key factors in p75MSC CdM that protected CPCs. Human CTGF peptide (CTGF-D4) and Insulin synergistically promoted CPC survival during hypoxia in culture. Similar to CdM priming, priming of CSCs with CTGF-D4 and Insulin for 30 minutes prior to transplantation promoted robust engraftment, survival, and migration of CSC derivatives at 1 week and 1 month after MI. Our results indicate that short-term priming of human CSCs with CTGF-D4 and Insulin may improve graft success and cardiac regeneration in patients with MI. Stem Cells 2014;32:674–683

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