Development of hybrid stem cell therapy for human heart failure

开发治疗人类心力衰竭的混合干细胞疗法

基本信息

批准号：
18390233
负责人：
OH Hidemasa
金额：
$ 10.91万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

To develop an efficient cell therapy for cardiac repair, we performed serial analysis of gene expression and identified follistatin, an antagonist of TGF-β family members, was predominantly expressed in skeletal muscle-derived progenitors. We have found that follistatin may be an effective progenitor-enhancing agent neutralizing ActA and GDF11 signaling to regulate the growth of progenitor cells in skeletal muscle. In addition, we demonstrate a single-cell deposition analysis to isolate individually selected cardiac stem cells from adult hearts and investigate the signals required for their proliferation and survival. Clonally proliferated cardiac stem cells 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 enriched … More for cells expressing Sca-1. Knockdown of Sca-1 transcripts in cardiac stem cells led to retarded ex vivo expansion and apoptosis through Akt inactivation. We also show that ongoing cardiac stem cell 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 be an essential component that promotes cardiac stem cell proliferation and survival to directly facilitate early engraftment, and that indirectly exerts the effects on late cardiovascular differentiation after cardiac stem cell transplantation. Based on these observations in rodents, we conducted two randomized, placebo-controlled studies in immunosuppressed pigs with anterior myocardial infarctions. As the results of these studies, we found that controlled delivery of bFGF modulates the post-ischemic microenvironment to enhance human cardiac stem cell engraftment and differentiation. This novel integrated-strategy demonstrates significantly functional improvements after myocardial infarction and could be a potentially safe and feasible application to treat human heart failure. Less

为了开发有效的细胞治疗以进行心脏修复，我们对基因表达进行了序列分析，并确定了TGF-β家族成员的拮抗剂Follistatin，主要在骨骼肌衍生的祖细胞中表达。我们发现，卵泡素可能是一种有效的祖细胞增强剂中和ACTA和GDF11信号传导，以调节骨骼肌中祖细胞的生长。此外，我们展示了单细胞沉积分析，以分离成人心脏中单独选择的心脏干细胞，并研究其增殖和生存所需的信号。带有胚胎干（ES）细胞和间充质细胞样特征的心脏干细胞的心脏增殖心脏干细胞表达干细胞抗原-1（SCA-1），并与远程酶逆转录酶（TERT）相关。使用在TERT启动子控制下表达GFP报告基因的转换，我们证明了TERT^<gfp+>级分来自心脏的含量……更多用于表达SCA-1的细胞。心脏干细胞中的SCA-1转录本的敲低导致通过AKT失活的离体扩张和凋亡。我们还表明，直接细胞植入缺血性心肌后，持续的心脏干细胞增殖和存活需要SCA-1，以上调增强新血管生成并限制心脏凋亡的分泌旁分泌作用。这是SCA-1可能是促进心脏干细胞增殖和存活以直接促进早期参与的重要组成部分，并间接发挥对晚期心脏干细胞移植的影响。基于啮齿动物中的这些观察结果，我们在具有心肌前违反的免疫抑制猪中进行了两项随机的安慰剂对照研究。作为这些研究的结果，我们发现BFGF的控制递送可调节缺血后的微环境，以增强人类心脏干细胞的植入和分化。这种新颖的综合策略表现出心肌梗塞后的功能改善，并且可能是治疗人体心力衰竭的潜在安全且可行的应用。较少的