| Project/Area Number |
18390233
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Kyoto University |
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Principal Investigator |
OH Hidemasa Kyoto University, Dep. Experimental Therapeutic, Associate Professor (50372579)
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| Co-Investigator(Kenkyū-buntansha) |
UEYAMA Tomomi Kyoto University, Dep. Experimental Therapeutic, Assistant Professor (80379388)
HARADA Koichiro Kyoto University, Dep. Experimental Therapeutic, Assistant Professor (30402902)
OAGATA Takehiro Kyoto University, Dep. Experimental Therapeutic, Research Associate (10402877)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥17,050,000 (Direct Cost: ¥15,700,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2007: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2006: ¥11,200,000 (Direct Cost: ¥11,200,000)
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| Keywords | cardiac stem cells / autologous transplantation / heart failure / stem cell growth factor / tissue engineering / 再生医療 / 心筋幹細胞 / 生体吸収材料 / 臨床治験 / 細胞移植 |
|---|
| Research Abstract |
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
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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
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