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Biochim Biophys Acta. 2013 Dec;1832(12):2136-44. doi: 10.1016/j.bbadis.2013.08.002. Epub 2013 Aug 16.

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

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Medical Research Center for Ischemic Tissue Regeneration, School of Medicine, Pusan National University, Yangsan, Republic of Korea; Department of Physiology, School of Medicine, Pusan National University, Yangsan, Republic of Korea.


Mesenchymal stem cells (MSCs) accelerate regeneration of ischemic or injured tissues by stimulation of angiogenesis through a paracrine mechanism. Tumor necrosis factor-α (TNF-α)-activated MSCs secrete pro-angiogenic cytokines, including IL-6 and IL-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-α-activated MSCs. Intramuscular injection of conditioned medium derived from TNF-α-treated MSCs (TNF-α 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 TNF-α CM-stimulated tissue repair, blood perfusion, and angiogenesis. In addition, TNF-α 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-α CM into the ischemic limb led to augmented homing of tail vein-injected EPCs into the ischemic limb in vivo and immunodepletion of IL-6 or IL-8 from TNF-α CM attenuated TNF-α 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-α CM stimulates angiogenesis and tissue repair through an increase in homing of EPCs through paracrine mechanisms involving IL-6 and IL-8.


Angiogenesis; EPCs; Endothelial progenitor cells; Ischemia; MSCs; Mesenchymal stem cells; TNF-α; TNF-α CM; Tumor necrosis factor-α; conditioned medium derived from TNF-α-treated MSCs; endothelial progenitor cells; hASCs; human adipose tissue-derived MSCs; mesenchymal stem cells; tumor necrosis factor-α

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