期刊
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
卷 58, 期 10, 页码 4344-4354出版社
ASSOC RESEARCH VISION OPHTHALMOLOGY INC
DOI: 10.1167/iovs.17-21506
关键词
mesenchymal stem cells; TSG-6; corneal epithelial stem/progenitor cells; wound healing; macrophage polarization; diabetes
资金
- National Natural Science Foundation of China [81470610, 81670829, 81570820, 81500702]
- Shandong Provincial Nature Science Fund [2016ZRC03122, ZR2015HQ005]
- Science and Technology Fund from Shinan District [2016-3-008-YY]
- Innovation Project of Shandong Academy of Medical Sciences
- Shandong Provincial Nature Science Fund for Distinguished Young Scholars [JQ201518]
- Taishan Scholar Program [20150215, 20161059]
PURPOSE. To explore the role and mechanism of bone marrow-derived mesenchymal stem cells (BM-MSCs) in corneal epithelial wound healing in type 1 diabetic mice. METHODS. Diabetic mice were treated with subconjunctival injections of BM-MSCs or recombinant tumor necrosis factor-a-stimulated gene/protein-6 (TSG-6). The corneal epithelial wound healing rate was examined by fluorescein staining. The mRNA and protein expression levels of TSG-6 were measured by quantitative RT-PCR and Western blot. The infiltrations of leukocytes and macrophages were analyzed by flow cytometry and immunofluoresence staining. The effect of TSG-6 was further evaluated in cultured limbal epithelial stem/progenitor cells, macrophages, and diabetic mice by short hairpin RNA (shRNA) knockdown. RESULTS. Local MSC transplantation significantly promoted diabetic corneal epithelial wound healing, accompanied by elevated corneal TSG-6 expression, increased corneal epithelial cell proliferation, and attenuated inflammatory response. Moreover, in cultured human limbal epithelial stem/progenitor cells, TSG-6 enhanced the colony-forming efficiency, stimulated mitogenic proliferation, and upregulated the expression level of DNp63. Furthermore, in diabetic mouse cornea and in vitro macrophage culture, TSG-6 alleviated leukocyte infiltration and promoted the polarization of recruited macrophages to anti-inflammatory M2 phenotypes with increased phagocytotic capacity. In addition, the promotion of epithelial stem/progenitor cell activation and macrophage polarization by MSC transplantation was largely abrogated by shRNA knockdown of TSG-6. CONCLUSIONS. This study provided the first evidence of TSG-6 secreted by MSCs promoting corneal epithelial wound healing in diabetic mice through activating corneal epithelial stem/progenitor cells and accelerating M2 macrophage polarization.
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