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首页> 外文学位 >Biomechanical promotion of mesenchymal stem cell proliferation as a countermeasure to the development of obesity and osteoporosis.
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Biomechanical promotion of mesenchymal stem cell proliferation as a countermeasure to the development of obesity and osteoporosis.

机译：促进间充质干细胞增殖的生物力学作为肥胖症和骨质疏松症发展的对策。

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摘要

Pluripotent mesenchymal stem cells (MSCs) are considered ideal therapeutic targets in regenerative medicine, as they hold the capacity to differentiate into osteoblasts, adipocytes, fibroblasts, chondrocytes, and myocytes. The potential to harness MSCs as a means of prevention and treatment of disease is dependent on an improved understanding of the means by which exogenous signals regulate their activity, and the ability of these stimuli to influence either/both proliferation and differentiation This work addressed the hypothesis that MSCs represent a common mechano-responsive element upstream of osteoblast and adipocyte differentiation that could potentially be targeted for the control and treatment of both obesity and osteoporosis. We proposed that low magnitude mechanical signals (LMMS) could non-pharmacologically and non-invasively promote stem cell proliferation, and thus an organism's healing and regenerative potential.;In light of the increased health complications experienced by obese individuals, we assessed the impact of a high fat diet on the resident stem cell population, as a possible contributing factor in the pathophysiology of obesity. We show that the MSC population was significantly diminished in animals fed a high fat diet for six weeks. Data from flow cytometry and real-time PCR provided clear indication that while the high fat diet decreased the MSC population, LMMS increased the proliferation of MSC's and was able to recover the diet-induced decrease in cell numbers. In addition, the marrow environment in LMMS animals had shifted towards osteogenesis both in cell number and gene expression, providing a mechanism of LMMS action based on the selective differentiation of MSC's into osteoprogenitors.;To characterize the phenotypic effects of twelve weeks of LMMS stimulation on a young adult animal, we developed a methodology for in vivo micro-computed tomography (microCT) for the precise determination of fat quantity, and more importantly fat distribution in the body. We applied these in vivo imaging methods to a complete characterization of the phenotypic fat suppression under normal dietary conditions, and several models of dietary induced obesity. Finally, data from a long term study (36 week of LMMS treatment) provided preliminary evidence of the benefit of LMMS in mitigating some the deleterious effects of dietary induced obesity and aging.;The experiments and results presented herein indicate that MSCs respond to LMMS by increasing proliferation. A developmentally mediated mechanism by which fat was suppressed and bone was enhanced, was implicated and was linked to the mechanically-based biasing of the mesenchymal stem cells to preferentially differentiate towards osteoblasts over adipocytes. The mechanical promotion of the number of progenitor cells, as well as driving commitment choices, suggests a means to enhance an organism's regenerative capacity as achieved by exploiting stem cell sensitivity to physical signals.
机译：多能间充质干细胞（MSC）被认为是再生医学的理想治疗靶标，因为它们具有分化为成骨细胞，脂肪细胞，成纤维细胞，软骨细胞和肌细胞的能力。利用MSC预防和治疗疾病的潜力取决于对外源信号调节其活动的方式的更好理解，以及这些刺激影响增殖和分化的能力。这项工作解决了这一假设MSC代表成骨细胞和脂肪细胞分化上游的常见机械反应元件，可能成为控制和治疗肥胖症和骨质疏松症的靶标。我们提出低强度机械信号（LMMS）可以非药理学和非侵入性地促进干细胞增殖，从而促进生物体的愈合和再生潜能。；鉴于肥胖个体所遇到的健康并发症增加，我们评估了对常驻干细胞群的高脂肪饮食，可能是肥胖症病理生理的可能因素。我们显示，喂食高脂饮食六周的动物中MSC种群显着减少。来自流式细胞仪和实时PCR的数据清楚地表明，尽管高脂饮食减少了MSC群体，但LMMS增加了MSC的增殖，并能够恢复饮食诱导的细胞数量减少。此外，LMMS动物的骨髓环境在细胞数量和基因表达上都向成骨性转变，从而基于MSC选择性分化为骨祖细胞提供了LMMS作用的机制。表征LMMS刺激十二周对小鼠的表型效应作为一种年轻的成年动物，我们开发了一种用于体内微计算机断层扫描（microCT）的方法，该方法可精确确定脂肪量，更重要的是确定体内脂肪的分布。我们将这些体内成像方法应用于正常饮食条件下表型脂肪抑制的完整表征，以及饮食诱发肥胖的几种模型。最后，来自长期研究（LMMS治疗36周）的数据提供了LMMS在减轻饮食诱发的肥胖和衰老的某些有害作用方面的益处的初步证据。此处的实验和结果表明MSC通过以下方式对LMMS做出反应增加扩散。牵涉一种发育介导的机制，通过该机制抑制脂肪并增强骨骼，并与间充质干细胞基于机械的偏向相联系，从而优先分化为成骨细胞而不是脂肪细胞。机械促进祖细胞数量以及推动选择承诺，提出了一种通过利用干细胞对物理信号的敏感性来增强生物体再生能力的方法。

著录项

  • 作者

    Luu, Yen Kim.;

  • 作者单位

    State University of New York at Stony Brook.;

  • 授予单位 State University of New York at Stony Brook.;
  • 学科 Biology, Molecular.;Biology, Cell.;Engineering, Biomedical.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 162 p.
  • 总页数 162
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;细胞生物学;生物医学工程;
  • 关键词

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