© 2008 European Society of Cardiology
Characterization of the paracrine effects of human skeletal myoblasts transplanted in infarcted myocardium
a Hematology, Cardiology and Cell Therapy, Clinica Universitaria and Division of Cancer, Foundation for Applied Medical Research, Division of Cancer, University of Navarra Pamplona, Spain
b University Paris 7, Department of Biochemistry EA 300, Paris, France
c AP-HP, Hôpital Européen Georges Pompidou, Department of Cardiology; University Paris Descartes, Faculty of Medicine INSERM U 633; Paris, France
d AP-HP, Hôpital Européen Georges Pompidou, Department of Cardiovascular Surgery; University Paris Descartes, Faculty of Medicine INSERM U 633; Paris, France
* Corresponding author. Hematology and Cell Therapy, Clinica Universitaria, Av Pio XII 36, Pamplona 31008, Spain. Tel.: +34 948 255 400. E-mail address: fprosper{at}unav.es (F. Prósper)
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Abstract |
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Background: The discrepancy between the functional improvements yielded experimentally by skeletal myoblasts (SM) transplanted in infarcted myocardium and the paucity of their long-term engraftment has raised the hypothesis of cell-mediated paracrine mechanisms.
Methods and results: We analyzed gene expression and growth factors released by undifferentiated human SM (CD56+), myotubes (SM cultured until confluence) and fibroblasts-like cells (CD56–). Gene expression revealed up-regulation of pro-angiogenic (PGF), antiapoptotics (BAG-1, BCL-2), heart development (TNNT2, TNNC1) and extracellular matrix remodelling (MMP-2, MMP-7) genes in SM. In line with the gene expression profile, the analysis of culture supernatants of SM by ELISA identified the release of growth factors involved in angiogenesis (VEGF, PIGF, angiogenin, angiopoietin, HGF and PDGF-BB) as well as proteases involved in matrix remodelling (MMP2, MMP9 and MMP10) and their inhibitors (TIMPs). Culture of smooth muscle cells (SMC), cardiomyocytes (HL-1) and human umbilical vein endothelial cells (HUVECs) with SM-released conditioned media demonstrated an increased proliferation of HUVEC, SMC and cardiomyocytes (p<0.05) and a decrease in apoptosis of cardiomyocytes (p<0.05). Analysis of nude rats transplanted with human SM demonstrated expression of human-specific MMP-2, TNNI3, CNN3, PGF, TNNT2, PAX7, TGF-β, and IGF-1 1 month after transplant.
Conclusions: Our data support the paracrine hypothesis whereby myoblast-secreted factors may contribute to the beneficial effects of myogenic cell transplantation in infarcted myocardium.
Key Words: Skeletal myoblast • Paracrine • Cell therapy • Myocardial infarction
Received March 17, 2008; Revised June 26, 2008; Accepted August 18, 2008
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