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Identification of MFGE8 in mesenchymal stem cell secretome as an anti-fibrotic factor in liver fibrosis
Yu Jin Jang1, Su Yeon An1, Jong-Hoon Kim1,*
1Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences & Biotechnology, Korea University, Seoul 02841, Republic of Korea
Abstract
Beneficial paracrine roles of mesenchymal stem cells (MSCs) in tissue repairs promise potential therapeutic strategies against different diseases. However, key therapeutic factors secreted from MSCs and their exact molecular mechanisms of action are not well defined. We found that the cell-free secretome of umbilical cord-derived MSCs had significant anti-fibrotic activity in mouse models of liver fibrosis. Our study demonstrated that the reduction in fibrosis was achieved by perturbing hepatic stellate cell activation by directly inhibiting TGFモ/Smad-signaling. Importantly, the anti-fibrotic effects of MSC secretome were blocked in vitro and in vivo by antagonizing milk fat globule-EGF factor 8 (MFGE8) activity. Furthermore, we showed that MFGE8 was secreted by MSCs not only from umbilical cord, but also from other tissues, including teeth and bone marrow. We proved that administration of recombinant MFGE8 protein alone had a significant anti-fibrotic effect using two different models of liver fibrosis. Additionally, the MFGE8 downregulated TGFモ type I receptor expression by binding to メvモ3 integrin on HSCs. These findings uncover a potential new role of MFGE8 in modulating TGFモ-signaling and suggest that MFGE8 could serve as a novel therapeutic agent for liver fibrosis.
Abstract, Accepted Manuscript(in press) [Submitted on January 23, 2017, Accepted on January 23, 2017]
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