Cardiac Repair of Severe Heart Failure by Human Heart- or Skeletal Muscle-Derived Multipotent Stem Cells

人类心脏或骨骼肌来源的多能干细胞对严重心力衰竭的心脏修复

• 批准号: 17209028
• 负责人: MATSUBARA Hiroaki
• 金额: $ 31.7万
• 依托单位: Kyoto Prefectural University of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17209028/
• 关键词: cardiac stem cell; heart failure; regeneration; cardiomyogenesis; 血管新生; 多能性幹細胞; 心筋前駆細胞; 血管前駆細胞

Recent studies have shown that cardiac stem cells (CSCs) from the adult heart can give rise to functional cardiomyocytes; however, the definite surface markers to identify a definitive single entity of CSCs and the molecular mechanisms regulating their growth have remained unknown. Here we demonstrate a single-cell deposition analysis to isolate individually selected CSCs from adult hearts and investigate the signals required for their proliferation and survival. Clonally proliferated CSCs express stem cell antigen-1 (Sca-1) with embryonic stem (ES) cell-and mesenchymal cell-like characteristics and are associated with telomerase reverse transcriptase (TERT). Using a transgene that expresses a GFP reporter under the control of the TERT promoter, we demonstrated that TERT^<GFP+> fractions from the heart were entiched for cell expressing Sca-1. Knockdown of Sca-1 transcripts in CSCs led to retarded ex vivo expansion and apoptosis through Akt inactivation. We also show that ongoing CSC proliferation and survival after direct cell-grafting into ischemic myocardium require Sca-1 to upregulate the secreted paracrine effectors that augment neoangiogenesis and limit cardiac apoptosis, Thus, Sca-1 might bean essential component that promotes CSC proliferation and survival to directly facilitate early engraftment, and that indirectly exerts the effects on late cardiovascular differentiation after CSC transplantation.

最近的研究表明，来自成年心脏的心脏干细胞（CSCs）可以产生功能性心肌细胞;然而，用于识别CSCs的明确单一实体的明确表面标记物以及调节其生长的分子机制仍然未知。在这里，我们展示了一个单细胞沉积分析，以分离单独选择的CSC从成人心脏和调查所需的信号，为他们的增殖和生存。克隆增殖的CSC表达具有胚胎干（ES）细胞和间充质细胞样特征的干细胞抗原-1（Sca-1），并与端粒酶逆转录酶（TERT）相关。使用在TERT启动子控制下表达GFP报告基因的转基因，我们证明了来自心脏的TERT-GFP+级分被诱导用于表达Sca-1的细胞。CSCs中Sca-1转录物的敲低通过Akt失活导致离体扩增和凋亡延迟。我们还发现，CSC直接移植到缺血心肌后的增殖和存活需要Sca-1上调分泌的旁分泌效应物，这些旁分泌效应物增加新血管生成并限制心脏凋亡。因此，Sca-1可能是促进CSC增殖和存活以直接促进早期移植的重要成分，并间接影响CSC移植后的晚期心血管分化。

项目成果

Carbon dioxide-rich water bathing enhances collateral blood flow in ischemic hindlimb via mobilization of endothelial progenitor cells and activation of NO-cGMP system

• DOI: 10.1161/01.cir.0000159329.40098.66
• 发表时间: 2005-03-29
• 期刊: CIRCULATION
• 影响因子: 37.8
• 作者: Irie, H;Tatsumi, T;Matsubara, H
• 通讯作者: Matsubara, H

Myocarium-targeted delivery of endothelial progenitor cells by ultrasound-mediated microbubble destruction improves cardiac function via an angiogenic respon

通过超声介导的微泡破坏对内皮祖细胞进行心肌靶向递送，通过血管生成反应改善心脏功能

• 发表时间: 2006
• 期刊: J Mol Cell Cardiol 40
• 作者: Zen;K.;Matsubara;H
• 通讯作者: H

Sonoporation using microbubble BR14 promotes pDNA/siRNA transduction to marine heart

使用微泡 BR14 的声孔促进 pDNA/siRNA 转导至海洋心脏

• 发表时间: 2005
• 期刊: Biochem Biophys Res Commun 336
• 作者: Tsunoda S;Matsubara H(他7人、6番目著者)
• 通讯作者: Matsubara H(他7人、6番目著者)

Overexpression of Tie2-promoted Activated Fibroblast Growth Factor Receptor 2 in Endothelial Cells enhances Angiogenesis and Induces Cardioprotective Effect via Src-Akt-Hifla Signaling Pathway in Mice Myocardial Infarction

Tie2 促进的活化成纤维细胞生长因子受体 2 在内皮细胞中过表达可增强小鼠心肌梗死中的血管生成并通过 Src-Akt-Hifla 信号通路诱导心脏保护作用

• 发表时间: 2007
• 作者: Matsunaga;S.;Tatsumi;T.;Okigaki;M.;Kishita;E.;Kimata;M.;Honsyo;S.;Takeda;M.;Nishikawa;S.;Matoba;S.;Kobara;M.;Matsubara;H
• 通讯作者: H

Bone Marrow Angiotensin ^ Typel Receptor Augments Atherosclerosis by Promoting Monocyte/Macrophage Lineage Differentiation form Hematopoietic Stem Cells

骨髓血管紧张素^1型受体通过促进造血干细胞的单核细胞/巨噬细胞谱系分化来增强动脉粥样硬化

• 发表时间: 2007
• 作者: Tsubakimoto;Y.;Yamada;H. Yokoi;H.;Takata;H.;Kawahito;H.;Hirai;H.;Imanishi;J.;Ashihara;E.;Maekawa;T.;Takahashi;T.;Okigaki;M.;Matsubara;H
• 通讯作者: H