TSG-6 Released from Intradermally Injected Mesenchymal Stem Cells Accelerates Wound Healing and Reduces Tissue Fibrosis in Murine Full-Thickness Skin Wounds

Proper activation of macrophages (M phi) in the inflammatory phase of acute wound healing is essential for physiological tissue repair. However, there is a strong indication that robust M phi inflammatory responses may be causal for the fibrotic response always accompanying adult wound healing. Using a complementary approach of in vitro and in vivo studies, we here addressed the question of whether mesenchymal stem cells (MSCs)-due to their anti-inflammatory properties-would control M phi activation and tissue fibrosis in a murine model of full-thickness skin wounds. We have shown that the tumor necrosis factor-alpha (TNF-alpha)-stimulated protein 6 (TSG-6) released from MSCs in co-culture with activated M phi or following injection into wound margins suppressed the release of TNF-alpha from activated M phi and concomitantly induced a switch from a high to an anti-fibrotic low transforming growth factor-beta 1 (TGF-1 beta)/TGF-beta 3 ratio. This study provides insight into what we believe to be a previously undescribed multifaceted role of MSC-released TSG-6 in wound healing. MSC-released TSG-6 was identified to improve wound healing by limiting M phi activation, inflammation, and fibrosis. TSG-6 and MSC-based therapies may thus qualify as promising strategies to enhance tissue repair and to prevent excessive tissue fibrosis.