HMGB1-stimulated human primary cardiac fibroblasts exert a paracrine action on human and murine cardiac stem cells

J Mol Cell Cardiol. 2008 Apr;44(4):683-93. doi: 10.1016/j.yjmcc.2008.01.009. Epub 2008 Feb 13.


High Mobility Box 1 Protein (HMGB1) is a cytokine released into the extracellular space by necrotic cells and activated macrophages in response to injury. We recently demonstrated that HMGB1 administration into the mouse heart during acute myocardial infarction induces cardiac tissue regeneration by activating resident cardiac c-kit+ cells (CSCs) and significantly enhances left ventricular function. In the present study it was analyzed the hypothesis that human cardiac fibroblasts (cFbs) exposed to HMGB1 may exert a paracrine effect on mouse and human CSCs. Human cFbs expressed the HMGB1 receptor RAGE. Luminex technology and ELISA assays revealed that HMGB1 significantly enhanced VEGF, PlGF, Mip-1alpha, IFN-gamma, GM-CSF, Il-10, Il-1beta, Il-4, Il-1ra, Il-9 and TNF-alpha in cFbs cell culture medium. HMGB1-stimulated cFbs conditioned media induced CSC migration and proliferation. These effects were significantly higher to those obtained when HMGB1 was added directly to the culture medium. In conclusion, we provide evidence that HMGB1 may act in a paracrine manner stimulating growth factor, cytokine and chemokine release by cFbs which, in turn, modulate CSC function. Via this mechanism HMGB1 may contribute to cardiac tissue regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Chemokines / metabolism
  • Culture Media, Conditioned
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Fibroblasts / cytology*
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • HMGB1 Protein / pharmacology*
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins
  • Mice
  • Myocardium / cytology*
  • Myocardium / metabolism
  • Paracrine Communication / drug effects*
  • Phenotype
  • Proteins / metabolism
  • Stem Cells / cytology*
  • Stem Cells / drug effects*
  • Vascular Endothelial Growth Factor A / metabolism


  • Chemokines
  • Culture Media, Conditioned
  • HMGB1 Protein
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • PIGF protein, human
  • Proteins
  • Vascular Endothelial Growth Factor A