Heparanase released from mesenchymal stem cells activates integrin beta1/HIF-2alpha/Flk-1 signaling and promotes endothelial cell migration and angiogenesis.
Heparanase released from mesenchymal stem cells activates integrin beta1/HIF-2alpha/Flk-1 signaling and promotes endothelial cell migration and angiogenesis.
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从间充质干细胞释放的肝素酶激活整联蛋白beta1/hif-2alpha/flk-1信号传导，并促进内皮细胞迁移和血管生成。
DOI：
10.1002/stem.1995
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发表时间：
2015-06
期刊：
影响因子：
5.2
通讯作者：
Wang, Jian'an
中科院分区：
文献类型：
--
作者：
Hu, Xinyang;Zhang, Ling;Jin, Jing;Zhu, Wei;Xu, Yinchuan;Wu, Yan;Wang, Yingchao;Chen, Han;Webster, Keith A.;Chen, Huiqiang;Yu, Hong;Wang, Jian'an
乙酰肝素酶在肿瘤血管生成中起重要作用。我们以前的研究表明，低氧预处理（HPC）增强了间充质干细胞（MSCs）的血管生成和治疗作用，这种作用被增强的乙酰肝素酶表达所抵消。本研究旨在阐明乙酰肝素酶在改善HPC-MSCs治疗特性中的作用，并使用缺血大鼠后肢模型探索其潜在机制。通过肌内注射将用乙酰肝素酶（MSChpa）或空载体（MSCnull）转染的MSC递送至缺血后肢。与MSCnull相比，接受MSChpa的后肢在7天时更快地恢复血流，并在14天时获得更高的毛细血管密度。与MSCnull组相比，来自MSChpa的条件培养基增加了内皮细胞迁移并促进了更大的管形成。经MSChpa条件培养液处理后，人脐静脉内皮细胞（HUVECs）中血管内皮生长因子受体2（VEGFR 2，Flk-1）及其下游信号通路（p38 MAPK/HSP 27）的表达明显增加。与MSChpa-KD条件培养基共培养可降低这些反应。通过染色质免疫沉淀-PCR和荧光素酶测定，MSChpa条件培养基激活缺氧诱导因子-2 α（HIF-2α）并平行增加Flk-1的转录水平。整合素β1在HIF-2α表达调控中起重要作用。MSChpa条件培养基的所有血管生成作用均通过选择性shRNA敲低HUVECs中的整合素β1、HIF-2α和Flk-1而消除。这些发现确定肝素酶是MSC血管生成的关键调节因子。我们提出了一种新的途径，其中乙酰肝素酶依次激活整合素β1、HIF-2α、Flk-1和p38 MAPK/HSP 27，并相应地增强血管生成。
Heparanase plays important roles in tumor angiogenesis. Our previous study demonstrated that hypoxic preconditioning (HPC) enhanced the angiogenic and therapeutic effects of mesenchymal stem cells (MSCs), effects that were paralleled by enhanced heparanase expression. This study was designed to elucidate the role of heparanase in the improved therapeutic properties of HPC-MSCs and to explore underlying mechanisms using an ischemic rat hind limb model. MSCs transfected with heparanase (MSChpa) or empty vector (MSCnull) were delivered by intramuscular injections to ischemic hind limbs. Hind limbs that received MSChpa recovered blood flow more rapidly at 7 days and acquired higher capillary density at 14 days compared with MSCnull. Conditioned medium from MSChpa increased endothelial cell migration and promoted greater tube formation relative to that from the MSCnull groups. Vascular endothelial growth factor receptor 2 (VEGFR2, Flk-1) and its downstream signaling pathway (p38MAPK/HSP27) were significantly increased in human umbilical vein endothelial cells (HUVECs) after treatment with MSChpa conditioned medium. Each of these responses was decreased by cocultured with MSChpa-KD conditioned medium. MSChpa conditioned medium activated hypoxia-inducible factor-2α (HIF-2α) and increased in parallel the transcript level of Flk-1 as determined by chromatin immunoprecipitation-PCR and luciferase assays. Analyses of integrin expression revealed an important role for integrin β1 in the regulation of HIF-2α. All angiogenic effects of MSChpa conditioned medium were abolished by knockdown of integrin β1, HIF-2α, and Flk-1 in HUVECs with selective shRNAs. These findings identify heparanse as a key regulator of angiogenesis by MSCs. We propose a novel pathway wherein heparanse sequentially activates integrin β1, HIF-2α, Flk-1, and p38MAPK/HSP27 with corresponding enhancement of angiogenesis.
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影响因子：
9.8
作者：
Han, Yu;Yang, Ke;Proweller, Aaron;Zhou, Guangjin;Jain, Mukesh K.;Ramirez-Bergeron, Diana L.
通讯作者：
Ramirez-Bergeron, Diana L.
影响因子：
4.8
作者：
Keely, Simon;Glover, Louise E.;Colgan, Sean P.
通讯作者：
Colgan, Sean P.
通过下调乙酰肝素酶抑制内质网应激诱导的乳腺癌细胞侵袭和迁移
影响因子：
5.4
作者：
Li, Yang;Liu, Hao;Jiang, Zhi Wen
通讯作者：
Jiang, Zhi Wen
影响因子：
4.8
作者：
Gingis-Velitski, S;Zetser, A;Ilan, N
通讯作者：
Ilan, N
影响因子：
4.8
作者：
Kim, Hyun-Yi;Yang, Dong-Hwa;Choi, Kang-Yell
通讯作者：
Choi, Kang-Yell