Harnessing mechanical signals to control mesenchymal stem cell fate

利用机械信号控制间充质干细胞的命运

• 批准号: 8371760
• 负责人: Stefan Judex
• 金额: $ 35.97万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8371760
• 关键词: Acceleration; Adipocytes; Adipose tissue; Animal Model; Animals; Architecture; Biological; Biomedical Engineering; Biophysics; Bone Marrow; Bone Marrow Stem Cell; Cell Lineage; Cell Nucleus; Cell physiology; Cells; Cellular Structures; Chronic Disease; Cilia; Clinic; Clinical; Cytoskeleton; Development; Diabetes Mellitus; Diet; Disease; Elements; Engineering; Environment; Estrogens; Exercise; Exposure to; Fatty Liver; Fatty acid glycerol esters; Focal Adhesions; Frequencies; Goals; Health Promotion; Hour; Human; Hypertriglyceridemia; In Vitro; Inflammation; Intervention; Knowledge; Liquid substance; Liver diseases; Marrow; Mechanics; Medicine; Mesenchymal; Mesenchymal Stem Cells; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Molecular Biology; Mus; Muscle; Musculoskeletal; Nonesterified Fatty Acids; Obesity; Osteogenesis; Osteopenia; Osteoporosis; Outcome; Ovariectomy; Pathologic; Pathology; Pathway interactions; Phenotype; Process; Proto-Oncogene Proteins c-akt; Recovery; Regulation; Regulatory T-Lymphocyte; Repression; Research Personnel; Rest; Schedule; Science; Signal Transduction; Stem cells; Stimulus; Strenuous Exercise; Sum; System; T-Lymphocyte Subsets; Time; Tissues; Translating; Variant; Visceral; Work; adipokines; base; bone; bone cell; design; disorder control; glucose tolerance; high risk; human disease; improved; in vivo; indexing; insulin sensitivity; lipid biosynthesis; mouse model; non-drug; prevent; progenitor; response; skeletal; stem cell differentiation; stem cell fate; stem cell population; subcutaneous; vibration

DESCRIPTION (provided by applicant): Exercise inhibits fat formation, and serves as a stimulus to form bone and muscle. While increased calorie use during strenuous activity helps to suppress fat accumulation, we have found that adipogenesis in vitro, and adiposity in vivo can also be inhibited in a calorie independent manner by mechanically biasing mesenchymal stem cells (MSCs) to favor differentiation towards a musculoskeletal, rather than an adipose fate. The ability to define stem cell lineage by mechanical signals suggests that a 'developmental' rather than a 'metabolic' strategy could be employed to prevent and/or treat diseases such as obesity, diabetes and osteoporosis. In marked contrast to bone/fat outcomes generated by prolonged exercise, we have shown that Low Intensity Vibration (LIV) produces an anabolic response in bone and a marked suppression of fat after short daily treatment time (<20 minutes per day) with high frequency (30-90Hz), extremely low intensity (<1.0g) mechanical signals. Translating this mechanosensitivity to the clinic, LIV can be delivered to the standing human with high efficiency (~70%), and is considered safe by both ISO and NIOSH for exposures up to 4 hours each day. This BRP is designed to improve our understanding of the physical and biological basis of regulating MSC fate with mechanical signals, and thereby improve our ability to translate this to the clinic as an "optimized" non- drug based intervention to prevent or reverse obesity and diabetes, while simultaneously suppressing osteopenia. Through three integrated specific aims, this BRP will examine the: 1) Biologic Mechanism of LIV: using primary MSCs, we will define specific molecular pathways which control - and maximize - the biologic responsiveness of MSC populations to these mechanical signals (e.g., incorporating recovery periods between mechanical bouts allows for amplification of the biologic response), with efforts to define which components of cell architecture contribute to the response; 2) Optimization of LIV Signal: by integrating finite element modeling with in vitro studies, we will work towards establishing the mechanical environment to which MSC are exposed during LIV, and identify those specific parameters that contribute to the efficacy of the LIV signal, providing the basis for optimizing the LIV signal. 3) Translational Potential of LIV: a the level of the whole animal, examine the degree to which optimized LIV signal and scheduling suppresses the fat phenotype in mouse models of diet-induced obesity and estrogen deficiency (ovariectomy), achieved through the regulation of MSC activity, and the extent to which downstream complications of diabesity, including insulin sensitivity, tissue steatosis, elevated triglycerides, free fatty acids and adipokines, are mitigated through exposure to LIV over extended periods of time. In sum, this BRP lies at the convergence of engineering, molecular biology, biophysics and medicine to understand how mechanical signals regulate MSC cell fate, with the ultimate goal of harnessing this sensitivity towards a bioengineering based, non-pharmacologic intervention for the suppression of diabesity, particularly excess visceral adiposity, in those at high risk for obesity and diabetes. PUBLIC HEALTH RELEVANCE: This BRP is designed, through three interconnected specific aims, to better understand how low intensity vibration (LIV) effectively bias mesenchymal stem cell differentiation away from adipogenesis (fat formation) and towards osteoblastogenesis (bone formation), and to establish whether this science can translate to the clinic as a non-pharmacological intervention to suppress chronic diseases such as diabesity.

描述（由申请人提供）：运动抑制脂肪的形成，并用作形成骨骼和肌​​肉的刺激。尽管在剧烈活性期间使用卡路里的使用增加有助于抑制脂肪的积累，但我们发现，体外的脂肪形成，体内的肥大性也可以通过机械偏置间充质干细胞（MSC）偏向于肌肉骨骼而不是脂肪命运而偏向于分化的体内抑制。通过机械信号来定义干细胞谱系的能力表明，可以采用“发育”而不是“代谢”策略来预防和/或治疗诸如肥胖，糖尿病和骨质疏松症之类的疾病。在与长时间运动产生的骨/脂肪结局的明显形成鲜明对比中，我们表明，低强度振动（LIV）在骨骼中产生合成代谢反应，并在短期治疗时间短（每天<20分钟）高频（30-90Hz）后对脂肪产生明显的抑制，强度极低（<1.0G）的机械信号。将这种机械敏感性转换为诊所，LIV可以以高效率（约70％）传递到站立的人，并且被ISO和NIOSH认为每天最多4个小时的暴露都被认为是安全的。该BRP旨在提高我们对使用机械信号调节MSC命运的物理和生物学基础的理解，从而提高我们将其转化为临床的能力，以“优化”的非药物基于基于药物的干预措施，以预防或逆转肥胖症和糖尿病，同时抑制骨质骨质。通过三个集成的特定目的，该BRP将研究以下：1）LIV的生物学机制：使用主要MSC，我们将定义特定的分子途径，这些特定分子途径控制并最大化 - MSC种群对这些机械信号的生物学反应性对这些机械信号的生物学反应性（例如，在机械响应之间恢复恢复时期，可以构成构造的构造，从而使恢复之间的恢复能力结合起来，从而构成了构造的构造，从而构成了构造的构造; 2）优化LIV信号：通过将有限元建模与体外研究相结合，我们将致力于建立LIV期间MSC暴露的机械环境，并确定那些有助于LIV信号功效的特定参数，从而为优化LIV信号提供了基础。 3）LIV的翻译潜力：A整个动物的水平，检查优化的LIV信号和调度的程度可在饮食引起的肥胖和雌激素缺乏症的小鼠模型中抑制脂肪表型，并通过调节MSC活性调节以及在包括糖尿病的下降效果的程度，包括胰岛素的效果，并具有胰岛素的影响，并具有胰岛素的影响，并具有胰岛素的影响力，并具有胰岛素的影响。酸和脂肪因子在长时间内暴露于LIV来减轻。总而言之，该BRP在于工程，分子生物学，生物物理学和药物的收敛性，以了解机械信号如何调节MSC细胞命运，其最终目的是利用这种对基于生物工程的，非药物干预的敏感性，以抑制糖尿病，尤其是糖尿病的抑制，肥胖症和肥胖症。 公共卫生相关性：该BRP通过三个相互联系的特定目的设计，以更好地理解低强度振动（LIV）如何有效地偏向间质干细胞从脂肪生成（脂肪形成）和成骨细胞生成（骨形成）（骨形成）（骨形成）的差异，并确定该科学是否可以转化为临床上的临床症状，以抑制抑制临床疗法，以抑制抑制症状疗法。