间充质干细胞
纤维化
生物
促炎细胞因子
炎症
癌症研究
川地163
肿瘤坏死因子α
骨髓
免疫学
间质细胞
M2巨噬细胞
病理
巨噬细胞
细胞生物学
医学
体外
生物化学
作者
Jason A. Horton,Kathryn Hudak,Eun Joo Chung,Ayla O. White,Bradley T. Scroggins,Jeffrey F. Burkeen,Deborah E. Citrin
出处
期刊:Stem Cells
[Wiley]
日期:2013-07-29
卷期号:31 (10): 2231-2241
被引量:104
摘要
Abstract Exposure to ionizing radiation (IR) can result in the development of cutaneous fibrosis, for which few therapeutic options exist. We tested the hypothesis that bone marrow-derived mesenchymal stem cells (BMSC) would favorably alter the progression of IR-induced fibrosis. We found that a systemic infusion of BMSC from syngeneic or allogeneic donors reduced skin contracture, thickening, and collagen deposition in a murine model. Transcriptional profiling with a fibrosis-targeted assay demonstrated increased expression of interleukin-10 (IL-10) and decreased expression of IL-1β in the irradiated skin of mice 14 days after receiving BMSC. Similarly, immunoassay studies demonstrated durable alteration of these and several additional inflammatory mediators. Immunohistochemical studies revealed a reduction in infiltration of proinflammatory classically activated CD80+ macrophages and increased numbers of anti-inflammatory regulatory CD163+ macrophages in irradiated skin of BMSC-treated mice. In vitro coculture experiments confirmed that BMSC induce expression of IL-10 by activated macrophages, suggesting polarization toward a regulatory phenotype. Furthermore, we demonstrated that tumor necrosis factor-receptor 2 (TNF-R2) mediates IL-10 production and transition toward a regulatory phenotype during coculture with BMSC. Taken together, these data demonstrate that systemic infusion of BMSC can durably alter the progression of radiation-induced fibrosis by altering macrophage phenotype and suppressing local inflammation in a TNF-R2-dependent fashion.
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