...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells
【24h】

Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells

机译：连接蛋白43通过将活性氧转移到骨髓基质细胞中来防止造血干细胞衰老

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Hematopoietic stem cell (HSC) aging has become a concern in chemotherapy of older patients. Humoral and paracrine signals from the bone marrow (BM) hematopoietic microenvironment (HM) control HSC activity during regenerative hematopoiesis. Connexin-43 (Cx43), a connexin constituent of gap junctions (GJs) is expressed in HSCs, down-regulated during differentiation, and postulated to be a self-renewal gene. Our studies, however, reveal that hematopoietic-specific Cx43 deficiency does not result in significant long-term competitive repopulation deficiency. Instead, hematopoietic Cx43 (H-Cx43) deficiency delays hematopoietic recovery after myeloablation with 5-fluorouracil (5-FU). 5-FU-treated H-Cx43-deficient HSC and progenitors (HSC/P) cells display decreased survival and fail to enter the cell cycle to proliferate. Cell cycle quiescence is associated with down-regulation of cyclin D1, up-regulation of the cyclin-dependent kinase inhibitors, p21~(cip1), and p16~(INK4a), and Forkhead transcriptional factor 1 (Foxoi), and activation of p38 mitogen-activated protein kinase (MAPK), indicating that H-Cx43-deficient HSCs are prone to senescence. The mechanism of increased senescence in H-Cx43-deficient HSC/P cells depends on their inability to transfer reactive oxygen species (ROS) to the HM, leading to accumulation of ROS within HSCs. In vivo antioxidant administration prevents the defective hematopoietic regeneration, as well as exogenous expression of Cx43 in HSC/P cells. Furthermore, ROS transfer from HSC/P cells to BM stromal cells is also rescued by reexpression of Cx43 in HSC/P. Finally, the deficiency of Cx43 in the HM phenocopies the hematopoietic defect in vivo. These results indicate that Cx43 exerts a protective role and regulates the HSC/P ROS content through ROS transfer to the HM, resulting in HSC protection during stress hematopoietic regeneration.
机译：造血干细胞（HSC）老化已成为老年患者化疗的关注点。在再生造血过程中，来自骨髓（BM）造血微环境（HM）的体液和旁分泌信号控制HSC活性。连接蛋白43（Cx43），间隙连接（GJs）的连接蛋白成分在HSC中表达，在分化过程中被下调，并被假定为自我更新基因。然而，我们的研究表明，造血特异性Cx43缺乏症不会导致长期的长期竞争性人口再缺乏症。相反，用5-氟尿嘧啶（5-FU）消融后，造血Cx43（H-Cx43）缺乏会延迟造血恢复。 5-FU处理的H-Cx43缺陷型HSC和祖细胞（HSC / P）的存活率下降，无法进入细胞周期进行增殖。细胞周期的静止与细胞周期蛋白D1的下调，细胞周期蛋白依赖性激酶抑制剂p21〜（cip1）和p16〜（INK4a）和Forkhead转录因子1（Foxoi）的上调以及p38的激活有关丝裂原激活蛋白激酶（MAPK），表明H-Cx43缺陷型HSC易于衰老。 H-Cx43缺乏的HSC / P细胞衰老增加的机制取决于其无法将活性氧（ROS）转移至HM，从而导致ROS在HSC内积累。体内抗氧化剂的给药可防止造血系统再生不良，以及Cx43在HSC / P细胞中的外源表达。此外，还可以通过在HSC / P中重新表达Cx43来挽救从HSC / P细胞向BM基质细胞的ROS转移。最后，HM表型中Cx43的缺乏复制了体内的造血功能缺陷。这些结果表明Cx43发挥保护作用，并通过将ROS转移至HM来调节HSC / P ROS含量，从而在应激性造血再生过程中提供HSC保护。

著录项

  • 来源
  • 作者

    Eri Taniguchi Ishikawa; Daniel Gonzalez-Nieto; Gabriel Ghiaur; Susan K. Dunn; Ashley M. Ficker; Bhuvana Murali; Malav Madhu; David E. Gutstein; Glenn I. Fishman; Luis C. Barrio; Jose A. Cancelas;

  • 作者单位

    Research Division, Hoxworth Blood Center, University of Cincinnati, Cincinnati, OH 45267;

    Stem Cell Program, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 Bioengineering and Telemedicine Group, Center for Biomedical Technology, Universidad Politecnica de Madrid, 28040 Madrid, Spain;

    Stem Cell Program, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;

    Research Division, Hoxworth Blood Center, University of Cincinnati, Cincinnati, OH 45267;

    Stem Cell Program, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;

    Stem Cell Program, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;

    Stem Cell Program, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;

    Leon H. Chamey Division of Cardiology, New York University School of Medicine, New York, NY 10016 Merck Sharp & Dohme Corporation, Rahway, NJ, 07065;

    Leon H. Chamey Division of Cardiology, New York University School of Medicine, New York, NY 10016;

    Unit of Experimental Neurology, Department of Research, Hospital Ramon y Cajal, 28034 Madrid, Spain;

    Research Division, Hoxworth Blood Center, University of Cincinnati, Cincinnati, OH 45267 Stem Cell Program, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    gja1; stem cell niche;

    机译：gja1;干细胞生态位;

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号