Human Stem Cells Overexpressing miR-21 Promote Angiogenesis in Critical Limb Ischemia by Targeting CHIP to Enhance HIF-1 Activity
Human Stem Cells Overexpressing miR-21 Promote Angiogenesis in Critical Limb Ischemia by Targeting CHIP to Enhance HIF-1 Activity
复制标题
人类干细胞过表达 Mir-21 通过靶向 CHIP 增强 HIF-1α 活性来促进危重肢体缺血症的血管生成
DOI：
10.1002/stem.2321
复制
发表时间：
2016-04-01
期刊：
影响因子：
5.2
通讯作者：
Zou, Duohong
中科院分区：
文献类型：
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作者：
Zhou, Yong;Zhu, Youming;Zou, Duohong
严重肢体缺血（CLI）是下肢动脉的严重阻塞。然而，CLI的有效和最佳治疗仍有待阐明。以前的治疗研究主要集中在促血管生成生长因子的管理。最近，miR-21已被揭示在血管生成中起关键作用。因此，我们假设miR-21在人脐带血来源的间充质干细胞（UCBMSCs）中的过表达可以有效地治疗CLI。本文中，用慢病毒-miR-21-荧光素酶（Lenti-miR-21）或慢病毒-LacZ-荧光素酶（Lenti-LacZ）转导UCBMSC。结果表明，miR-21在体外诱导UCBMSCs增殖、迁移和血管生成。分别于术后1、4、7、14、28 d进行大体观察和激光多普勒血流灌注成像检测。与生理盐水或Lenti-LacZ组相比，Lenti-miR-21组在第7天缺血肢体的血管有显著改善。在第28天，组织学分析证实过表达miR-21的UCBMSCs增加CLI中的新血管形成。此外，发现Hsc 70相互作用蛋白（CHIP）的羧基端是miR-21介导的UCBMSCs中缺氧诱导因子1（HIF-1）活化的靶基因。总之，我们的研究表明，在UCBMSCs中过表达miR-21可以通过靶向CHIP增强HIF-1活性来改善CLI中的新生血管形成，这可能在治疗CLI中具有巨大的治疗前景。干细胞2016;34：924-934
Critical limb ischemia (CLI) is a severe blockage in the arteries of the lower extremities. However, the effective and optimal treatment for CLI remains to be elucidated. Previous therapeutic research is mainly focused on proangiogenic growth factors administrations. Recently, miR-21 has been revealed to play a crucial role in angiogenesis. Thus, we hypothesize that miR-21 over-expression in human umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) can effectively treat CLI. Herein, UCBMSCs were transduced with lentivirus-miR-21-Luciferase (Lenti-miR-21) or lentivirus- LacZ-Luciferase (Lenti-LacZ). The results indicated that miR-21 induced UCBMSCs proliferation, migration, and angiogenesis in vitro. Subsequently, general observation and laser Doppler perfusion imaging were introduced to detect perfusion in muscles of CLI-nude mice on 1, 4, 7, 14, and 28 day postoperation. There was a significant improvement in blood vessels of the ischemic limb in Lenti-miR-21 group at 7 day compared with the saline or Lenti-LacZ groups. At 28 day, histological analysis confirmed that UCBMSCs over-expressing miR-21 increased neovascularization in CLI. Furthermore, carboxyl terminus of Hsc70-interacting protein (CHIP) was found to be the target gene for miR-21-mediated activation of hypoxia-inducible factor 1 (HIF-1) in UCBMSCs. In summary, our study demonstrated that over-expressing miR-21 in UCBMSCs could improve neovascularization in CLI through enhancing HIF-1 activity by targeting CHIP, which may hold great therapeutic promise in treating CLI. Stem Cells2016;34:924-934