Development of tailor-made regenerative therapy for heart failure by using autologous bone marrow stem cells

利用自体骨髓干细胞开发针对心力衰竭的定制再生疗法

基本信息

  • 批准号:
    16390397
  • 负责人:
  • 金额:
    $ 7.94万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
  • 财政年份:
    2004
  • 资助国家:
    日本
  • 起止时间:
    2004 至 2005
  • 项目状态:
    已结题

项目摘要

Cardiovascular regeneration by the implantation of autologous bone marrow stem cells is expected as an effective new therapy for serious heart failure. However, there are various cases as a cause of heart failure, such as myocardial ischemia, cardiomyopathy, or others. So, it is requested to develop a tailor-made therapy for heart failure by the implantation of autologous bone marrow stem cells, according to each patient's condition.At first, we tried to regenerate infarcted myocardium by implanting ex vivo TGF-β-preprogrammed CD117 (c-kit)-positive (CD117^+) bone marrow stem cells. CD117^+ cells were isolated from the bone marrow mononuclear cells of GFP-transgenic or normal C57/BL6 mice. The myogenic differentiation of CD117^+ cells was achieved by cultivation with TGF-β. We found that TGF-beta increased the cellular expression of myosin, troponins, connexin-43, GATA-4, and NKx-2.5, which suggested that it induced the myogenic differentiation of CD117^+ cells. Using an acute myocardi … More al infarction model, we also tried to regenerate infarcted myocardium by implanting untreated (newly isolated) or preprogrammed (24 hours of cultivation with 5 ng/mL TGF-β_1) CD117^+ cells intramyocardially. Histological analysis revealed newly regenerated myocardium in the left ventricular anterior wall after the implantation of TGF-β-preprogrammed cells but not untreated cells. Furthermore, the left ventricular percent fraction shortening was significantly higher after the implantation of TGF-β-preprogrammed cells than after the implantation of untreated CD117^+ cells. These results indicated that ex vivo TGF-β-preprogramming increased the myogenic differentiation of CD117^+ stem cells, which contributed to improved potency for the myocardial regeneration.Secondly, we tried to enhance the angiogenic potential of bone marrow cells by ex vivo hypoxia stimulation before implantation. Bone marrow cells were collected and cultured under hypoxia (2% O_2) or normoxia conditions. Cells were also injected into the ischemic hindlimb of rats after 24 h of culture. Hypoxia culture increased the mRNA expression of VEGF, VE-cadherin, and Flk-1 from 2.5- to five-fold in bone marrow cells. The microvessel density and blood flow rate in the ischemic hindlimbs were also significantly higher 2 weeks after implantation with hypoxia-cultured cells than with normoxia-cultured cells. These results indicated that ex vivo hypoxia pre-stimulation increased the VEGF mRNA expression and endothelial differentiation of bone marrow cells, which contributed to improved potency for the induction of therapeutic angiogenesis.Ex vivo pre-treatment of the marrow stem cell by TGF-β or hypoxia was able to improve their effect for regenerating injured myocardium or vessels, respectively. It seemed that the tailor-made therapy for heart failure could be developed by different ex vivo pre-treatments of bone marrow stem cells before implantation. Less
自体骨髓干细胞移植再生心血管有望成为治疗严重心力衰竭的有效新方法。然而,存在各种情况作为心力衰竭的原因,诸如心肌缺血、心肌病等。因此,需要根据患者的具体情况,通过移植自体骨髓干细胞来治疗心力衰竭。首先,我们尝试通过体外移植TGF-β-preprogrammed CD 117(c-kit)-positive(CD 117 ^+)骨髓干细胞来再生梗死心肌。从GFP转基因或正常C57/BL 6小鼠的骨髓单个核细胞中分离出CD 117 ^+细胞。用TGF-β诱导CD 117 ^+细胞向肌细胞分化。我们发现TGF-β可增加肌球蛋白、肌钙蛋白、连接蛋白-43、加塔-4和NKx-2.5的表达,这表明TGF-β可诱导CD 117 ^+细胞的肌源性分化。使用急性心肌 ...更多信息 在急性心肌梗死模型中,我们还尝试通过心肌内植入未处理的(新分离的)或预编程的(用5 ng/mL TGF-β_1培养24小时)CD 117 ^+细胞来再生梗死心肌。组织学分析显示,植入TGF-β-预编程细胞后,左心室前壁新生心肌,而非未处理细胞。此外,植入TGF-β-预编程细胞后左心室缩短百分比显著高于植入未经处理的CD 117 ^+细胞后。这些结果表明,体外TGF-β预编程可提高CD 117 ^+干细胞的成肌分化能力,从而提高其心肌再生能力。其次,我们尝试在植入前通过体外低氧刺激来增强骨髓细胞的血管生成能力。收集骨髓细胞,在低氧(2%O_2)或常氧条件下培养。培养24小时后,将细胞注射到大鼠缺血后肢中。低氧培养增加了骨髓细胞中VEGF、VE-钙粘蛋白和Flk-1的mRNA表达,从2.5倍增加到5倍。缺氧培养的细胞移植2周后,缺血后肢的微血管密度和血流速度也明显高于常氧培养的细胞。上述结果表明,低氧预刺激可提高骨髓干细胞VEGF mRNA的表达和内皮细胞的分化,从而提高其诱导治疗性血管生成的能力; TGF-β或低氧预处理骨髓干细胞可分别提高其促进损伤心肌或血管再生的作用。通过对骨髓干细胞移植前进行不同的体外预处理,可以为心力衰竭患者提供量身定制的治疗方案。少

项目成果

期刊论文数量(14)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cellular expression of integrin-beta1 is of critical importance for inducing therapeutic angiogneesis by cell implantation.
整合素-β1 的细胞表达对于通过细胞植入诱导治疗性血管生成至关重要。
Cellular expression of integrin-beta1 is of critical importance for inducing therapeutic angiogenesis by cell implantation.
整合素-β1 的细胞表达对于通过细胞植入诱导治疗性血管生成至关重要。
  • DOI:
  • 发表时间:
    2005
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Li TS;et al.;Li TS et al.
  • 通讯作者:
    Li TS et al.
Cellular expression of integrin-betal is of critical importance for inducing therapeutic angiogenesis by cell implantation.
整合素-β1 的细胞表达对于通过细胞植入诱导治疗性血管生成至关重要。
Pravastatin improves remodeling and cardiac function after myocardial infarction by an antiinflammatory mechanism rather than by the induction of angiogenesis
  • DOI:
    10.1016/j.athoracsur.2005.12.065
  • 发表时间:
    2006-06-01
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    Li, Tao-Sheng;Takahashi, Masaya;Sellke, Frank W.
  • 通讯作者:
    Sellke, Frank W.
Regeneration of infarcted myocardium by intramyocardial implantation of ex vivo transforming growth factor-beta-preprogrammed bone marrow stem cells
通过离体转化生长因子-β预编程骨髓干细胞心肌内植入实现梗死心肌的再生
  • DOI:
  • 发表时间:
    2005
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Li TS;et al.
  • 通讯作者:
    et al.
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HAMANO Kimikazu其他文献

HAMANO Kimikazu的其他文献

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{{ truncateString('HAMANO Kimikazu', 18)}}的其他基金

Development of exosomes accumulating in ischemic tissues for angiogenesis
外泌体在缺血组织中积累以促进血管生成的发展
  • 批准号:
    19K22660
  • 财政年份:
    2019
  • 资助金额:
    $ 7.94万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
Development of vascular regeneration therapy by exosome derived from enhanced cells
利用增强细胞衍生的外泌体开发血管再生疗法
  • 批准号:
    19H03739
  • 财政年份:
    2019
  • 资助金额:
    $ 7.94万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Challenges to rejuvenate aged-cardiac stem cells by genome editing to develop next generation therapeutic strategies for heart failure.
通过基因组编辑使衰老的心脏干细胞恢复活力以开发下一代心力衰竭治疗策略的挑战。
  • 批准号:
    15K15508
  • 财政年份:
    2015
  • 资助金额:
    $ 7.94万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Development of transplantation therapy using hypoxically preconditioned cell sheets for lower limb ischemic ulcers
低氧预处理细胞片移植治疗下肢缺血性溃疡的进展
  • 批准号:
    15H04939
  • 财政年份:
    2015
  • 资助金额:
    $ 7.94万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Novel therapeutic strategies using autologous bone marrow-derived stem cells for vascular regeneration
使用自体骨髓干细胞进行血管再生的新治疗策略
  • 批准号:
    23390336
  • 财政年份:
    2011
  • 资助金额:
    $ 7.94万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Challenges to identify endogenous factors associating with cardiac regeneration in heart failure.
确定与心力衰竭心脏再生相关的内源性因素面临的挑战。
  • 批准号:
    23659673
  • 财政年份:
    2011
  • 资助金额:
    $ 7.94万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Identification of Risk Factors Related to Poor Angiogenic Potential of Bone Marrow Cells from Different Patients
鉴定与不同患者的骨髓细胞血管生成潜能差相关的危险因素
  • 批准号:
    20390370
  • 财政年份:
    2008
  • 资助金额:
    $ 7.94万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Identification of risk factors related to poor angiogenic potency of bone marrow cells from different patients
鉴定与不同患者的骨髓细胞血管生成能力差相关的危险因素
  • 批准号:
    18390378
  • 财政年份:
    2006
  • 资助金额:
    $ 7.94万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
THERAPEUTIC ANGIOGENESIS INDUCED BY AUTOLOGOUS BONE MARROW CELLS IMPLANTATION FOR THE TREATMENT OF ISCHEMIC DISEASES
自体骨髓细胞植入诱导治疗性血管生成治疗缺血性疾病
  • 批准号:
    13671391
  • 财政年份:
    2001
  • 资助金额:
    $ 7.94万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
NEW TREATMENT FOR MYOCARDIAL INFARCTION BY XENO-FETAL CARDIOMYOCYTE TRANSPLANTATION
异种胎儿心肌细胞移植治疗心肌梗死的新方法
  • 批准号:
    11671326
  • 财政年份:
    1999
  • 资助金额:
    $ 7.94万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)

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Preventive and Therapeutic Effects of Bone Marrow Stem Cell-Derived Exosomes on Spine Dural Fibrosis
骨髓干细胞源性外泌体对脊柱硬膜纤维化的预防和治疗作用
  • 批准号:
    10350148
  • 财政年份:
    2022
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Preventive and Therapeutic Effects of Bone Marrow Stem Cell-Derived Exosomes on Spine Dural Fibrosis
骨髓干细胞源性外泌体对脊柱硬膜纤维化的预防和治疗作用
  • 批准号:
    10620150
  • 财政年份:
    2022
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    $ 7.94万
  • 项目类别:
Development of a Novel Treatment for Refractory Ulcerative Colitis by Combined Bone Marrow Stem Cell Transplantation and Leukocytapheresis
通过骨髓干细胞移植和白细胞分离术联合开发治疗难治性溃疡性结肠炎的新疗法
  • 批准号:
    20K17626
  • 财政年份:
    2020
  • 资助金额:
    $ 7.94万
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    Grant-in-Aid for Early-Career Scientists
Analysis of neural functional recovery mechanism immediately after bone marrow stem cell transplantation for spinal cord injury
骨髓干细胞移植治疗脊髓损伤后即刻神经功能恢复机制分析
  • 批准号:
    16K10830
  • 财政年份:
    2016
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Development of the bone regenerative medicine with the porous carbonate apatite made from calcium sulfate and bone marrow stem cell
硫酸钙与骨髓干细胞制成的多孔碳酸盐磷灰石骨再生医学的开发
  • 批准号:
    16K11752
  • 财政年份:
    2016
  • 资助金额:
    $ 7.94万
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    Grant-in-Aid for Scientific Research (C)
Oxidized Low-density Lipoprotein Impairs Bone Marrow Stem Cell Survival
氧化低密度脂蛋白损害骨髓干细胞的存活
  • 批准号:
    9128038
  • 财政年份:
    2015
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    $ 7.94万
  • 项目类别:
Regenerative therapy for clitical limb ischemia using bone marrow stem cell cultured in microgravity
微重力培养骨髓干细胞再生治疗危肢缺血
  • 批准号:
    26670617
  • 财政年份:
    2014
  • 资助金额:
    $ 7.94万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Regenerative therapy for postoperative paraplegia after thoracic aortic surgery using bone marrow stem cell cultured in microgravity
微重力培养骨髓干细胞再生治疗胸主动脉术后截瘫
  • 批准号:
    26293312
  • 财政年份:
    2014
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    $ 7.94万
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Bone marrow stem cell therapy in multiple sclerosis: potential mechanisms of repair and protection
多发性硬化症的骨髓干细胞治疗:修复和保护的潜在机制
  • 批准号:
    MR/K004166/1
  • 财政年份:
    2013
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Investigating the neuroprotective and neuroregenerative properties of bone marrow stem cell mobilising drugs in Friedreich ataxia.
研究骨髓干细胞动员药物对弗里德赖希共济失调的神经保护和神经再生特性。
  • 批准号:
    MR/J012580/1
  • 财政年份:
    2012
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    $ 7.94万
  • 项目类别:
    Research Grant
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