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首页> 外文学位 >Mechanisms for the effects of adipose tissue-derived stromal/stem cells on angiogenesis and tissue repair in ischemic diseases.
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Mechanisms for the effects of adipose tissue-derived stromal/stem cells on angiogenesis and tissue repair in ischemic diseases.

机译：脂肪组织来源的基质/干细胞对缺血性疾病中血管生成和组织修复的影响机制。

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摘要

The use of therapeutic cell-types, such as stem and progenitor cells, has gained much interest as a potential therapeutic approach for ischemic regeneration, but the mechanisms are not fully understood. Adipose Tissue-derived Stromal/Stem Cells (ASCs) secrete physiologically relevant levels of HGF. The specific contribution of HGF to ASC potency was determined by silencing HGF expression. A dual-cassette lentiviral construct expressing GFP and either a small hairpin RNA (shRNA) specifically targeted to HGF mRNA (shHGF) or an inactive control sequence (shCtrl) were used to stably transduce ASCs. Transduced ASC-shHGF secreted less HGF, which led to a reduced ability to promote survival, proliferation and migration of mature and progenitor endothelial cells in vitro. ASC-shHGF were also significantly impaired, compared to ASC-shCtrl, in their ability to promote reperfusion in a mouse hindlimb ischemia model. The diminished ability of ASC-shHGF to promote reperfusion of ischemic tissues was reflected by reduced densities of capillaries in reperfused tissues. In addition, fewer ASCs were detected at 3 wk in ischemic limbs of mice treated with ASC-shHGF. In a second study, we have used a chronic cardiac ischemia model to assess the mechanisms of ASC-dependent tissue repair. ASCs or carrier alone were injected into the peri-infarct region and heart function was evaluated by serial echocardiography. Whereas, saline treated hearts showed significantly reduced function based on multiple parameters, ASC-treated rats consistently exhibited better cardiac function at 1 month compared to 4 days after LAD occlusion. Histological analysis demonstrated that ASC treated hearts had lower fibrosis and a higher small arteriole density. It was determined through immunofluorescent detection of HLA-ABC-expressing cells that human ASCs where present at one month and were predominantly localized to peri-infarct regions, but did not apparently differentiate into cardiomyocytes in significant numbers. In conclusion, we have demonstrated that ASCs have great potential as a cell therapy for tissue regeneration following ischemic insult. Given the abundant source of autologous ASCs, therapies with these cells have a higher potential for widespread adoption compared to rarer therapeutic cell types. Local factor secretion by donor cells is a key element of cell-based therapies.
机译：作为缺血再生的潜在治疗方法，使用治疗性细胞类型（例如干细胞和祖细胞）已引起了广泛的兴趣，但其机理尚未完全明了。脂肪组织来源的基质/干细胞（ASC）分泌HGF的生理相关水平。通过沉默HGF表达来确定HGF对ASC效能的特异性贡献。表达GFP和专门针对HGF mRNA（shHGF）的小发夹RNA（shRNA）或无活性的控制序列（shCtrl）的双盒式慢病毒构建体用于稳定转导ASC。转导的ASC-shHGF分泌的HGF较少，这导致体外促进成熟和祖细胞内皮细胞存活，增殖和迁移的能力降低。与ASC-shCtrl相比，ASC-shHGF在小鼠后肢缺血模型中促进再灌注的能力也显着受损。 ASC-shHGF促进缺血组织再灌注的能力减弱反映在再灌注组织中毛细血管密度降低。另外，在用ASC-shHGF治疗的小鼠的缺血肢体中，在3周时检测到较少的ASC。在第二项研究中，我们使用了慢性心脏缺血模型来评估ASC依赖性组织修复的机制。单独的ASC或载体被注入梗死周围区域，并通过连续超声心动图评估心脏功能。生理盐水处理的心脏由于多个参数而显示出明显降低的功能，而ASC处理的大鼠在1个月时的LAD闭塞后的4天始终表现出更好的心脏功能。组织学分析表明，经ASC治疗的心脏纤维化程度较低，小动脉密度更高。通过对表达HLA-ABC的细胞进行免疫荧光检测，可以确定人ASC存在一个月，主要位于梗死周围区域，但显然没有大量分化为心肌细胞。总之，我们证明了ASC作为缺血性损伤后组织再生的细胞疗法具有巨大的潜力。鉴于自体ASC的来源丰富，与罕见的治疗细胞类型相比，用这些细胞进行治疗的可能性更高。供体细胞分泌局部因子是基于细胞的疗法的关键要素。

著录项

  • 作者

    Cai, Liying.;

  • 作者单位

    Indiana University.;

  • 授予单位 Indiana University.;
  • 学科 Biology Physiology.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 172 p.
  • 总页数 172
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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