Pro-inflammatory cytokines activate hypoxia-inducible factor 3α via epigenetic changes in mesenchymal stromal/stem cells.
Pro-inflammatory cytokines activate hypoxia-inducible factor 3α via epigenetic changes in mesenchymal stromal/stem cells.
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DOI：
10.1038/s41598-018-24221-5
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发表时间：
2018-04-11
影响因子：
4.6
通讯作者：
Cobellis G
中科院分区：
文献类型：
--
作者：
Cuomo F;Coppola A;Botti C;Maione C;Forte A;Scisciola L;Liguori G;Caiafa I;Ursini MV;Galderisi U;Cipollaro M;Altucci L;Cobellis G
人间充质基质/干细胞（hMSCs）由于具有再生受损组织、促进血管生成和减少炎症的能力而成为一种很有前途的缺血性疾病治疗工具，导致令人鼓舞的结果，但仍然有限。探索hMSC治疗的临床试验结果受到受影响组织中低细胞保留和存活的影响，部分受病变微环境的影响，其中低氧条件（即缺氧）和炎症共存。缺氧和炎症是病理生理应激，具有共同的激活因子，如缺氧诱导因子（hif）和NF-κB。HIF1α和HIF2α主要响应缺氧，激活参与组织修复的途径。关于HIF3α的调控知之甚少。我们在体外和体内研究了HIF3α的作用。人间充质干细胞表达HIF3α，受促炎细胞因子以氧不依赖的方式差异调节，这是一种新的但尚未确定的机制，其中NF-κB对其表达至关重要。我们通过甲基化特异性PCR和组蛋白修饰研究了表观遗传修饰是否参与HIF3α的表达。在促炎细胞因子驱动下，在整个HIF3A位点观察到组蛋白H3的强烈高甲基化。小鼠动脉切开模型的实验显示，浸润炎性细胞中Hif3α的表达被激活，提示Hif3α在体内炎症中的新作用。
Human mesenchymal stromal/stem cells (hMSCs) emerged as a promising therapeutic tool for ischemic disorders, due to their ability to regenerate damaged tissues, promote angiogenesis and reduce inflammation, leading to encouraging, but still limited results. The outcomes in clinical trials exploring hMSC therapy are influenced by low cell retention and survival in affected tissues, partially influenced by lesion’s microenvironment, where low oxygen conditions (i.e. hypoxia) and inflammation coexist. Hypoxia and inflammation are pathophysiological stresses, sharing common activators, such as hypoxia-inducible factors (HIFs) and NF-κB. HIF1α and HIF2α respond essentially to hypoxia, activating pathways involved in tissue repair. Little is known about the regulation of HIF3α. Here we investigated the role of HIF3α in vitro and in vivo. Human MSCs expressed HIF3α, differentially regulated by pro-inflammatory cytokines in an oxygen-independent manner, a novel and still uncharacterized mechanism, where NF-κB is critical for its expression. We investigated if epigenetic modifications are involved in HIF3α expression by methylation-specific PCR and histone modifications. Robust hypermethylation of histone H3 was observed across HIF3A locus driven by pro-inflammatory cytokines. Experiments in a murine model of arteriotomy highlighted the activation of Hif3α expression in infiltrated inflammatory cells, suggesting a new role for Hif3α in inflammation in vivo.
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影响因子：
9
作者：
Pescatore A;Esposito E;Draber P;Walczak H;Ursini MV
通讯作者：
Ursini MV
DOI：
10.1016/j.bbrc.2006.11.027
发表时间：
2007-01-12
影响因子：
3.1
作者：
Heidbreder, Marc;Qadri, Fatimunnisa;Dominiak, Peter
通讯作者：
Dominiak, Peter
影响因子：
168.9
作者：
Dick, Katherine J.;Nelson, Christopher P.;Samani, Nilesh J.
通讯作者：
Samani, Nilesh J.
影响因子：
82.9
作者：
Ceradini, DJ;Kulkarni, AR;Gurtner, GC
通讯作者：
Gurtner, GC
缺氧在炎症性疾病中的作用（综述）。
影响因子：
5.4
作者：
Biddlestone J;Bandarra D;Rocha S
通讯作者：
Rocha S