Decorin-Modified Umbilical Cord Mesenchymal Stem Cells (MSCs) Attenuate Radiation-Induced Lung Injuries via Regulating Inflammation, Fibrotic Factors, and Immune Responses
Decorin-Modified Umbilical Cord Mesenchymal Stem Cells (MSCs) Attenuate Radiation-Induced Lung Injuries via Regulating Inflammation, Fibrotic Factors, and Immune Responses
复制标题
DOI：
10.1016/j.ijrobp.2018.04.007
复制
发表时间：
2018-07-15
影响因子：
7
通讯作者：
Wang, Hua
中科院分区：
文献类型：
--
作者：
Liu, Daming;Kong, Fanxuan;Wang, Hua
目的：评价核心蛋白聚糖(DCN)修饰的间充质干细胞(MSCs)对放射性肺损伤(RILI)的治疗作用，并探讨其作用机制。方法与材料：用Ad(E1-).DCN修饰脐带间充质干细胞(MSCs)，获得表达DCN的MSCs(DCN修饰MSCs[MSCs.DCN])。在实验性RILI小鼠模型中，分别于照射后6h或28d静脉接种MSCs.DCN和MSCs.Null[经Ad(E1-).Null修饰的MSCs]。照射后28天和3个月分别进行肺组织病理组织学检查，评价对肺组织炎症和纤维化的治疗效果。分析血清和肺组织中的炎性细胞因子和趋化因子，以及外周血和脾组织中包括调节性T细胞(Tregs)在内的T淋巴细胞亚群。结果：两种MSC治疗晚期均可通过减少淋巴细胞浸润、减少细胞凋亡、促进上皮细胞增殖、抑制纤维化而减轻组织病理损伤。然而，MSCs.DCN的治疗效果更令人印象深刻。此外，我们还发现，MSC治疗降低了外周血和肺组织中趋化因子和炎性细胞因子的表达，增加了抗炎细胞因子的表达。一个重要的发现是，MSCs.DCN在诱导干扰素-γ的表达、抑制肺组织中Ⅲ型胶原的表达以及降低Tregs的比例方面要有效得多。此外，我们的数据表明，照射后急性期(6h)的治疗在减轻炎症和抑制纤维化方面的反应明显强于后期(28d)。结论：MSCs.DCN可以减轻照射后的急性炎症反应，并显著抑制后期纤维化。同样，DCN通过靶向促纤维化因子和Tregs来增强MSCs的功能。(C)2018 Elsevier Inc.保留所有权利。
Purpose: To evaluate the therapeutic effects of decorin (DCN)-modified mesenchymal stem cells (MSCs) on radiation-induced lung injuries (RILIs) and to clarify the underlying mechanisms.Methods and Materials: Umbilical cord-derived mesenchymal stem cells (MSCs) were modified with Ad(E1-).DCN to generate DCN-expressing MSCs (DCN-modified MSCs [MSCs.DCN]). In an experimental mouse model of RILI, MSCs.DCN and MSCs.Null [MSCs modified with Ad(E1-).Null] were intravenously engrafted at 6 hours or 28 days after irradiation. The therapeutic effects on lung inflammation and fibrosis were evaluated by histopathologic analysis at 28 days and 3 months after irradiation. Inflammatory cytokines and chemokines were analyzed in both sera and lung tissues, and subtypes of T lymphocytes including regulatory T cells (Tregs) were analyzed in the peripheral blood and spleen.Results: Both MSC treatments could alleviate histopathologic injuries by reducing lymphocyte infiltration, decreasing apoptosis, increasing proliferation of epithelial cells, and inhibiting fibrosis in the later phase. However, treatment with MSCs.DCN resulted in much more impressive therapeutic effects. Moreover, we discovered that MSC treatment reduced the expression of chemokines and inflammatory cytokines and increased the expression of anti-inflammatory cytokines in both the peripheral blood and local pulmonary tissues. An important finding was that MSCs.DCN were much more effective in inducing interferon-y expression, inhibiting collagen type III al expression in pulmonary tissues, and decreasing the proportion of Tregs. Furthermore, our data suggested that treatment during the acute phase (6 hours) after irradiation evoked much stronger responses both in attenuating inflammation and in inhibiting fibrosis than in the later phase (28 days).Conclusions: MSCs.DCN could attenuate acute inflammation after irradiation and significantly inhibit later fibrosis. Likewise, DCN enhanced the functions of MSCs by targeting profibrotic factors and Tregs. (C) 2018 Elsevier Inc. All rights reserved.