Infarct Repair with Mesenchymal Stem Cell Subpopulation

间充质干细胞亚群修复梗塞

基本信息

  • 批准号:
    8469715
  • 负责人:
  • 金额:
    $ 35.94万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-08-08 至 2018-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The outcomes of cardiac repair with bone marrow mesenchymal stem cell (MSC), a highly heterogeneous cell population, have been variable and generally suboptimal. The efficacy of specific and homogenous MSC subsets defined by antigen expression has not been investigated. Based on preliminary data, our fundamental hypothesis states that transplantation of antigenically-defined CD45-/c-kit-/Sca- 1+/CD90+/CD105- (abbreviated as CD105-) MSC subpopulation will confer greater reparative and regenerative benefits after myocardial infarction (MI) by virtue of enhanced survival, increased retention, improved angiogenesis, greater differentiation into cardiac lineages, and favorable modulation of myocardial matrix. This hypothesis will be tested in a well-established cell culture model in vitro and a mouse model of reperfused MI in vivo, which will yield conclusive results. Aim 1 will determine whether CD105- MSCs will be more resistant to apoptosis and washout. The susceptibility of murine bone marrow MSCs (Unfractionated, CD45-/c-kit-/Sca-1+/CD90+/CD105+ [abbreviated as CD105+, the precise antigenic control population], and CD105-) to apoptosis will be examined, and the underlying molecular basis elucidated. The expression of adhesion molecules on MSCs will be assessed, and cell retention in vivo will be tested following myocardial injection 2 d after a reperfused MI. Aim 2 will investigate whether CD105- MSCs produce greater amounts of cardioprotective and angiogenic molecules, and acquire endothelial phenotype. Endothelial and cardiac commitment will be determined by morphology, and assessment of transcription factors and structural proteins. The molecular signaling underlying the angiogenic effects will be elucidated using specific inhibitors and siRNA, with particular attention to VEGFR2-activated pathways. Aim 3 will establish whether transplantation of CD105- MSCs will induce superior cardiac repair in vivo, and identify the mechanistic basis in a definitive fashion. Unfractionated, and CD105+ and CD105- MSCs will be injected into the infarct borderzone 2 d after a reperfused MI in C57BL/6 mice. Serial echocardiography and a terminal hemodynamic study will be performed to assess left ventricular (LV) function and anatomy. LV structure, infarct size, fibrosis, and myocyte hypertrophy will be assessed by morphometry. Quantitative immunohistochemical methods will be used to precisely determine the contribution of myocyte salvage from apoptosis, angiogenesis, myocyte proliferation, myocyte regeneration, activation of cardiac progenitors, and modulation of calcium handling proteins. Focused proteomic analysis will be performed to identify novel changes in the matrix. For the first time, these studies will critically evaluate th biology of CD105- MSC subset and their efficacy in infarct repair in a comprehensive and thoroughly mechanistic fashion. The impact will be two-fold: (i) biologically, this project will yild novel insights into properties of antigenically-defined MSC populations; and (ii) clinically, the identification and validation of an optimal cell type for cardiac repair will benefit patients with ischemic heart disease and post-MI heart failure.
描述(由申请人提供):高度异构细胞种群的骨髓间充质干细胞(MSC)的心脏修复结果已变化,通常是优越的。尚未研究由抗原表达定义的特定和同质MSC亚群的功效。基于初步数据,我们的基本假设指出,抗原定义的CD45-/c-kit-/sca-/sca- 1+/cd90+/cd90+/cd105-(作为CD105-缩写为CD105-)MSC亚群会通过增强了肌肉式(MSC)的增强后,并增强了在心肌依次(MI的恢复后),并增强了心肌的依赖(MI的增强)。更大的分化为心脏谱系和心肌基质的有利调节。该假设将在体外的体外建立的细胞培养模型和体内重新融合的MI的小鼠模型中进行检验,这将产生结论性的结果。 AIM 1将确定CD105-MSC是否对凋亡和冲洗性更具耐药性。鼠骨髓MSC的敏感性(未分流,CD45-/C-KIT-/SCA-1+/CD90+/CD105+[作为CD105+的缩写为CD105+,精确的抗原对照群体],CD105-)和对细胞凋亡的敏感性将被检查,并将检查基础的分子基础。将评估粘附分子在MSC上的表达,并在重新填充MI后2 d后在体内保留细胞在体内进行测试。 AIM 2将研究CD105- MSC是否产生更多的心脏保护性和血管生成分子,并获得内皮表型。内皮和心脏承诺将由形态学以及转录因子和结构蛋白的评估确定。将使用特定的抑制剂和siRNA阐明基于血管生成作用的分子信号传导,并特别注意VEGFR2激活的途径。 AIM 3将确定CD105-MSC的移植是否会在体内诱导出色的心脏修复,并以明确的方式识别机械基础。在C57BL/6小鼠中重新填充MI后,未分离,CD105+和CD105- MSC将2 d注射到梗塞边界区域。连续超声心动图和终末血液动力学研究将进行评估左心室(LV)功能和解剖结构。 LV结构,梗塞大小,纤维化和肌细胞肥大将通过形态计量法评估。定量免疫组织化学方法将用于精确确定凋亡,血管生成,肌细胞增殖,心肌再生,心脏祖细胞激活和钙处理蛋白质的调节所产生的心肌细胞挽救的贡献。将进行集中的蛋白质组学分析以识别基质中的新变化。这些研究将首次以全面且彻底的机械方式对CD105- MSC子集的TH生物学及其在梗塞修复中的疗效进行批判性评估。影响将是两个方面:(i)从生物学上讲,该项目将对抗原定义的MSC种群的特性有新颖的见解; (ii)在临床上,对心脏修复的最佳细胞类型的识别和验证将使患者受益 缺血性心脏病和MI后心力衰竭。

项目成果

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BUDDHADEB DAWN其他文献

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{{ truncateString('BUDDHADEB DAWN', 18)}}的其他基金

Infarct Repair with Mesenchymal Stem Cell Subpopulation
间充质干细胞亚群修复梗塞
  • 批准号:
    9912625
  • 财政年份:
    2019
  • 资助金额:
    $ 35.94万
  • 项目类别:
Infarct Repair with Mesenchymal Stem Cell Subpopulation
间充质干细胞亚群修复梗塞
  • 批准号:
    9264001
  • 财政年份:
    2013
  • 资助金额:
    $ 35.94万
  • 项目类别:
Infarct Repair with Mesenchymal Stem Cell Subpopulation
间充质干细胞亚群修复梗塞
  • 批准号:
    8826806
  • 财政年份:
    2013
  • 资助金额:
    $ 35.94万
  • 项目类别:
Infarct Repair with Mesenchymal Stem Cell Subpopulation
间充质干细胞亚群修复梗塞
  • 批准号:
    9047301
  • 财政年份:
    2013
  • 资助金额:
    $ 35.94万
  • 项目类别:
Infarct Repair with Mesenchymal Stem Cell Subpopulation
间充质干细胞亚群修复梗塞
  • 批准号:
    8717716
  • 财政年份:
    2013
  • 资助金额:
    $ 35.94万
  • 项目类别:
CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: CORE B
糖尿病和肥胖研究卓越中心:核心 B
  • 批准号:
    7960458
  • 财政年份:
    2009
  • 资助金额:
    $ 35.94万
  • 项目类别:
Organ protection during cardiopulmonary arrest
心肺骤停时的器官保护
  • 批准号:
    7468129
  • 财政年份:
    2008
  • 资助金额:
    $ 35.94万
  • 项目类别:
Isolation of novel mesenchymal stem cell subpopulations
新型间充质干细胞亚群的分离
  • 批准号:
    7472005
  • 财政年份:
    2008
  • 资助金额:
    $ 35.94万
  • 项目类别:
Organ protection during cardiopulmonary arrest
心肺骤停时的器官保护
  • 批准号:
    7789664
  • 财政年份:
    2008
  • 资助金额:
    $ 35.94万
  • 项目类别:
Isolation of novel mesenchymal stem cell subpopulations
新型间充质干细胞亚群的分离
  • 批准号:
    8038578
  • 财政年份:
    2008
  • 资助金额:
    $ 35.94万
  • 项目类别:

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Infarct Repair with Mesenchymal Stem Cell Subpopulation
间充质干细胞亚群修复梗塞
  • 批准号:
    8826806
  • 财政年份:
    2013
  • 资助金额:
    $ 35.94万
  • 项目类别:
Infarct Repair with Mesenchymal Stem Cell Subpopulation
间充质干细胞亚群修复梗塞
  • 批准号:
    9047301
  • 财政年份:
    2013
  • 资助金额:
    $ 35.94万
  • 项目类别:
Infarct Repair with Mesenchymal Stem Cell Subpopulation
间充质干细胞亚群修复梗塞
  • 批准号:
    8717716
  • 财政年份:
    2013
  • 资助金额:
    $ 35.94万
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啮齿类柠檬酸杆菌对顶端连接复合体蛋白质的调节
  • 批准号:
    7558928
  • 财政年份:
    2008
  • 资助金额:
    $ 35.94万
  • 项目类别:
Regulation of Proteins in the Apical Junctional Complex by Citrobacter rodentium
啮齿类柠檬酸杆菌对顶端连接复合体蛋白质的调节
  • 批准号:
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    2008
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