Mesenchymal Stem Cell Migration and Proliferation Are Mediated by Hypoxia-Inducible Factor-1α Upstream of Notch and SUMO Pathways.
Mesenchymal Stem Cell Migration and Proliferation Are Mediated by Hypoxia-Inducible Factor-1α Upstream of Notch and SUMO Pathways.
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DOI：
10.1089/scd.2016.0331
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发表时间：
2017-07-01
影响因子：
4
通讯作者：
Sepúlveda P
中科院分区：
文献类型：
--
作者：
Ciria M;García NA;Ontoria-Oviedo I;González-King H;Carrero R;De La Pompa JL;Montero JA;Sepúlveda P
间充质干细胞（MSC）在治疗几种疾病中是有效的。我们和其他人已经证明，缺氧或缺氧诱导因子1 α（HIF-1α）稳定化可以改善MSC的几种功能，包括细胞粘附，迁移和增殖，从而增加其治疗潜力。为了进一步探讨HIF-1α诱导MSCs表达的机制，我们研究了HIF-1 α与Notch信号通路的关系，观察到HIF-1α在MSCs中的过表达增加了Notch配体Jagged 1-2和Delta-like（Dll）1、Dll 3和Dll 4的蛋白水平，并且只有当该通路被激活时才能增强Notch信号通路。HIF与Notch的相互作用导致MSCs依赖Notch的迁移和铺展，而抑制γ-分泌酶则可消除这一作用。然而，HIF-1诱导的MSC增殖的增加不依赖于Notch信号传导。泛素家族成员，小泛素样修饰物（SUMO），在许多细胞过程中具有重要的功能，并已报道缺氧时SUMO 1蛋白水平增加。为了研究SUMO化在HIF/Notch串扰中的潜在参与，我们测量了一般SUMO化水平，并观察到表达HIF-1的MSC中SUMO化增加。此外，在SUMO化抑制剂的存在下，MSC的增殖和迁移减少，并且这种作用在HIF-MSC中特别强烈。免疫沉淀研究表明，在表达HIF-1的MSC中，Notch 1（N1 ICD）的细胞内结构域发生SUMO化，这有助于Notch通路的激活，并导致N1 ICD核转位水平的增加，如通过亚细胞分级分离所评估的。在具有稳定HIF-1α表达的HEK 293 T细胞中也观察到N1 ICD的SUMO化，表明这是真核细胞中的常见机制。总之，我们首次描述了N1 ICD的SUMO化，这是由HIF信号增强的。这些现象可能与MSC在缺氧或HIF稳定条件下的治疗效果有关。
Mesenchymal stem cells (MSCs) are effective in treating several pathologies. We and others have demonstrated that hypoxia or hypoxia-inducible factor 1 alpha (HIF-1α) stabilization improves several MSC functions, including cell adhesion, migration, and proliferation, thereby increasing their therapeutic potential. To further explore the mechanisms induced by HIF-1α in MSCs, we studied its relationship with Notch signaling and observed that overexpression of HIF-1α in MSCs increased protein levels of the Notch ligands Jagged 1–2 and Delta-like (Dll)1, Dll3, and Dll4 and potentiated Notch signaling only when this pathway was activated. Crosstalk between HIF and Notch resulted in Notch-dependent migration and spreading of MSCs, which was abolished by γ-secretase inhibition. However, the HIF-1-induced increase in MSC proliferation was independent of Notch signaling. The ubiquitin family member, small ubiquitin-like modifier (SUMO), has important functions in many cellular processes and increased SUMO1 protein levels have been reported in hypoxia. To investigate the potential involvement of SUMOylation in HIF/Notch crosstalk, we measured general SUMOylation levels and observed increased SUMOylation in HIF-1-expressing MSCs. Moreover, proliferation and migration of MSCs were reduced in the presence of a SUMOylation inhibitor, and this effect was particularly robust in HIF-MSCs. Immunoprecipitation studies demonstrated SUMOylation of the intracellular domain of Notch1 (N1ICD) in HIF-1-expressing MSCs, which contributed to Notch pathway activation and resulted in increased levels of N1ICD nuclear translocation as assessed by subcellular fractionation. SUMOylation of N1ICD was also observed in HEK293T cells with stabilized HIF-1α expression, suggesting that this is a common mechanism in eukaryotic cells. In summary, we describe, for the first time, SUMOylation of N1ICD, which is potentiated by HIF signaling. These phenomena could be relevant for the therapeutic effects of MSCs in hypoxia or under conditions of HIF stabilization.
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影响因子：
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