Tumor necrosis factor-α-activated mesenchymal stem cells promote endothelial progenitor cell homing and angiogenesis

Mesenchymal stem cells (MSCs) accelerate regeneration of ischemic or injured tissues by stimulation of angiogenesis through a paracrine mechanism. Tumor necrosis factor-alpha (TNF-alpha)-activated MSCs secrete proangiogenic cytokines, including IL-6 and 1L-8. In the present study, using an ischemic hindlimb animal model, we explored the role of IL-6 and IL-8 in the paracrine stimulation of angiogenesis and tissue regeneration by TNF-alpha-activated MSCs. Intramuscular injection of conditioned medium derived from TNF-alpha-treated MSCs (TNF2 alpha CM) into the ischemic hindlimb resulted in attenuated severe limb loss and stimulated blood perfusion and angiogenesis in the ischemic limb. Immunodepletion of IL-6 and IL-8 resulted in attenuated INF-alpha CMstimulated tissue repair, blood perfusion, and angiogenesis. In addition, TNF-alpha CM induced migration of human cord blood-derived endothelial progenitor cells (EPCs) through IL-6- and IL-8-dependent mechanisms in vitro. Intramuscular injection of TNF-ot CM into the ischemic limb led to augmented homing of tail veininjected EPCs into the ischemic limb in vivo and immunodepletion of IL-6 or IL-8 from TNF-alpha CM attenuated TNF-alpha CM-stimulated homing of EPCs. In addition, intramuscular injection of recombinant IL-6 and IL-8 proteins resulted in increased homing of intravenously transplanted EPCs into the ischemic limb and improved blood perfusion in vivo. These results suggest that TNF-alpha CM stimulates angiogenesis and tissue repair through an increase in homing of EPCs through paracrine mechanisms involving IL-6 and IL-8. (C) 2013 Elsevier B.V. All rights reserved.