Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis.
Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis.
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DOI：
10.1186/s13287-017-0730-z
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发表时间：
2017-12-06
影响因子：
7.5
通讯作者：
Goodman SB
中科院分区：
文献类型：
--
作者：
Lin T;Pajarinen J;Nabeshima A;Lu L;Nathan K;Jämsen E;Yao Z;Goodman SB
间充质干细胞（MSCs）具有免疫调节和组织再生的能力，这突出了它们在治疗炎症性骨疾病方面的潜在转化应用。msc介导的免疫调节由促炎细胞因子和病原体相关的分子模式如脂多糖（LPS）调节。先前的研究表明，MSCs暴露于干扰素γ (IFN-γ)和促炎细胞因子肿瘤坏死因子α (TNF-α)协同抑制t细胞活化。在本研究中，我们开发了一种新的MSCs预处理策略，通过LPS + TNF-α来优化MSCs对巨噬细胞极化的免疫调节能力。通过体外共培养模型，预处理MSCs增强了抗炎M2巨噬细胞标志物（精氨酸酶1和CD206）的表达，降低了炎症M1巨噬细胞标志物（TNF-α/IL-1Ra）的表达。与IFN-γ + TNF-α联合治疗或单独治疗对照组相比，MSCs对巨噬细胞的免疫调节作用显著增强。成骨分化增强，包括碱性磷酸盐活性和基质矿化，仅在LPS + TNF-α预处理的MSCs中观察到。机制研究表明，前列腺素E2 （PGE2）产生的增加与精氨酸酶1表达的增强有关。选择性环氧化酶-2抑制塞来昔布降低共培养巨噬细胞中PGE2的产生和精氨酸酶1的表达。这种新型的预处理间充质干细胞具有增强的免疫调节和骨再生潜力，可用于治疗炎性骨疾病，包括假体周围骨溶解、骨折愈合/不愈合和骨坏死。本文的在线版本（doi:10.1186/s13287-017-0730-z）包含补充材料，仅供授权用户使用。
Mesenchymal stem cells (MSCs) are capable of immunomodulation and tissue regeneration, highlighting their potential translational application for treating inflammatory bone disorders. MSC-mediated immunomodulation is regulated by proinflammatory cytokines and pathogen-associated molecular patterns such as lipopolysaccharide (LPS). Previous studies showed that MSCs exposed to interferon gamma (IFN-γ) and the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) synergistically suppressed T-cell activation. In the current study, we developed a novel preconditioning strategy for MSCs using LPS plus TNF-α to optimize the immunomodulating ability of MSCs on macrophage polarization. Preconditioned MSCs enhanced anti-inflammatory M2 macrophage marker expression (Arginase 1 and CD206) and decreased inflammatory M1 macrophage marker (TNF-α/IL-1Ra) expression using an in-vitro coculture model. Immunomodulation of MSCs on macrophages was significantly increased compared to the combination of IFN-γ plus TNF-α or single treatment controls. Increased osteogenic differentiation including alkaline phosphate activity and matrix mineralization was only observed in the LPS plus TNF-α preconditioned MSCs. Mechanistic studies showed that increased prostaglandin E2 (PGE2) production was associated with enhanced Arginase 1 expression. Selective cyclooxygenase-2 inhibition by Celecoxib decreased PGE2 production and Arginase 1 expression in cocultured macrophages. The novel preconditioned MSCs have increased immunomodulation and bone regeneration potential and could be applied to the treatment of inflammatory bone disorders including periprosthetic osteolysis, fracture healing/nonunions, and osteonecrosis. The online version of this article (doi:10.1186/s13287-017-0730-z) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Croes M;Oner FC;Kruyt MC;Blokhuis TJ;Bastian O;Dhert WJ;Alblas J
通讯作者：
Alblas J
影响因子：
2.6
作者：
Kim, Jaehyup;Hematti, Peiman
通讯作者：
Hematti, Peiman
影响因子：
12.4
作者：
Francois, Moira;Romieu-Mourez, Raphaelle;Galipeau, Jacques
通讯作者：
Galipeau, Jacques
影响因子：
6.2
作者：
Alexander, Kylie A.;Chang, Ming K.;Pettit, Allison R.
通讯作者：
Pettit, Allison R.
影响因子：
4
作者：
Lu, ZuFu;Wang, Guocheng;Zreiqat, Hala
通讯作者：
Zreiqat, Hala