Dynamic compaction of human mesenchymal stem/precursor cells into spheres self-activates caspase-dependent IL1 signaling to enhance secretion of modulators of inflammation and immunity (PGE2, TSG6, and STC1).
Dynamic compaction of human mesenchymal stem/precursor cells into spheres self-activates caspase-dependent IL1 signaling to enhance secretion of modulators of inflammation and immunity (PGE2, TSG6, and STC1).
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DOI：
10.1002/stem.1499
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发表时间：
2013-11
期刊：
影响因子：
5.2
通讯作者：
Prockop, Darwin J.
中科院分区：
文献类型：
--
作者：
Bartosh, Thomas J.;Yloestalo, Joni H.;Bazhanov, Nikolay;Kuhlman, Jessica;Prockop, Darwin J.
人间充质干细胞/前体细胞（MSC）与其他一些干细胞/祖细胞相似，当在悬滴中或在非粘附表面上培养时，它们紧凑成球体。MSC组装成球体改变了它们的许多特性，包括增强介导炎症和免疫反应的因子的分泌。在这里，我们证明了MSC自发聚集成球状结构后，注射到皮下气囊或腹膜的小鼠。这些结构类似于培养物中形成的MSC球体，这通过炎症调节因子TSG 6、STC 1和COX 2（产生PGE 2的关键酶）的基因表达增加来证明。为了确定所涉及的信号传导途径，使用悬滴培养物来跟踪细胞压实成球体时的时间依赖性变化。上调的基因包括IL 1 α/β的应激激活信号通路基因和Notch的接触依赖性信号通路基因。半胱天冬酶抑制剂降低了IL 1 A/B表达的上调，IL 1信号传导抑制剂降低了PGE 2、TSG 6和STC 1的产生。此外，抑制IL 1A/B表达和PGE 2分泌可抵消MSC球对刺激的巨噬细胞的抗炎作用。使用γ-分泌酶抑制剂的实验表明，Notch信号传导也是PGE 2产生所需的，而不是TSG 6或STC 1。结果表明，MSC组装成球体触发半胱天冬酶依赖性IL 1信号传导和炎症和免疫调节剂的分泌。体内类似的聚集可以解释在动物模型中施用细胞时观察到的一些效应。
Human mesenchymal stem/precursor cells (MSC) are similar to some other stem/progenitor cells in that they compact into spheres when cultured in hanging drops or on non-adherent surfaces. Assembly of MSC into spheres alters many of their properties, including enhanced secretion of factors that mediate inflammatory and immune responses. Here we demonstrated that MSC spontaneously aggregated into sphere-like structures after injection into a subcutaneous air pouch or the peritoneum of mice. The structures were similar to MSC spheres formed in cultures demonstrated by the increased expression of genes for inflammation-modulating factors TSG6, STC1, and COX2, a key enzyme in production of PGE2. To identify the signaling pathways involved, hanging drop cultures were used to follow the time-dependent changes in the cells as they compacted into spheres. Among the genes up-regulated were genes for the stress-activated signaling pathway for IL1α/β, and the contact-dependent signaling pathway for Notch. An inhibitor of caspases reduced the up-regulation of IL1A/B expression, and inhibitors of IL1 signaling decreased production of PGE2, TSG6 and STC1. Also, inhibition of IL1A/B expression and secretion of PGE2 negated the anti-inflammatory effects of MSC spheres on stimulated macrophages. Experiments with γ-secretase inhibitors suggested that Notch signaling was also required for production of PGE2 but not TSG6 or STC1. The results indicated that assembly of MSC into spheres triggers caspase-dependent IL1 signaling and the secretion of modulators of inflammation and immunity. Similar aggregation in vivo may account for some of the effects observed with administration of the cells in animal models.
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影响因子：
8
作者：
Imayoshi, Itaru;Shimojo, Hiromi;Sakamoto, Masayuki;Ohtsuka, Toshiyuki;Kageyama, Ryoichiro
通讯作者：
Kageyama, Ryoichiro
影响因子：
23.9
作者：
Ranganath, Sudhir H.;Levy, Oren;Inamdar, Maneesha S.;Karp, Jeffrey M.
通讯作者：
Karp, Jeffrey M.
影响因子：
3
作者：
Frith, Jessica E.;Thomson, Brian;Genever, Paul G.
通讯作者：
Genever, Paul G.
DOI：
10.1152/ajpheart.00219.2008
发表时间：
2008-12-01
影响因子：
4.8
作者：
Potapova, Irina A.;Doronin, Sergey V.;Cohen, Ira S.
通讯作者：
Cohen, Ira S.
Notch 和 TGF-β 信号通路之间的串扰由 Notch 胞内结构域与 Smad3 的相互作用介导。
影响因子：
7.8
作者：
Blokzijl, A;Dahlqvist, C;Reissmann, E;Falk, A;Moliner, A;Lendahl, U;Ibáñez, CF
通讯作者：
Ibáñez, CF