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

High Mobility Box I Protein (HMGB1) is a cytokine released into the extracellular space by necrotic cells and activated macrophages in response to injury. We recently demonstrated that HMGB I 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 HMGB I may exert a paracrine effect on mouse and human CSCs. Human cFbs expressed the HMGB I receptor RAGE. Luminex technology and ELISA assays revealed that HMGB I significantly enhanced VEGF, PIGF, Mip-1 alpha, IFN-gamma, GM-CSF, II-10, II-1 beta, II-4, II-1ra, II-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 HMGB I may act in a paracrine manner stimulating growth factor, cytokine and chemokine release by cFbs which, in turn, modulate CSC function. Via this mechanism HMGB I may contribute to cardiac tissue regeneration.