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MYOCARDIAL PLASTICITY OF HUMAN FAT-DERIVED STEM CELLS

人类脂肪干细胞的心肌可塑性

基本信息

批准号：
6771813
负责人：
ADAM J. KATZ
金额：
$ 22.2万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-30 至 2007-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The promise of regenerative stem cell therapies are not likely to achieve clinical translation without the identification of an abundant, readily available, non-controversial source of cells. Our lab has identified adipose tissue as such a candidate cell source. A population of cells from human adipose tissue displays multi-lineage developmental plasticity in vitro, including adipogenic, osteogenic, chondrogenic, neurogenic and myogenic potential. Adipose tissue, more than any other primary human adult tissue, has the potential to enable the translation of autologous cell-based paradigms to the clinic because of its abundance, ease of harvest, appeal, expendability, and non-controversial nature. This proposal will specifically explore the cardiomyogenic potential of human adipo-derived cells within three settings: 1) in vitro, 2) in uninjured myocardium, and 3) in infarcted myocardium. This will be done with a multidisciplinary team consisting of clinicians, researchers and engineers that span the fields of plastic surgery, radiology, cardiac physiology, cell and molecular biology and biomedical engineering. The in vivo studies will employ a mouse model of left ventricular remodeling secondary to reperfused myocardial infarction (MI) that has already been established at UVA by the co-investigator. Using this model, the effects of cell transplantation on both global and regional myocardial function after MI will be assessed in a serial, non-invasive manner using state-of-the-art magnetic resonance imaging (MRI) coupled with advanced techniques of myocardial tagging. The specific aims of this proposal are: 1) Explore and characterize the cardiomyogenic potential of human adipo-derived cells (hADCs) in the in vitro setting. The cells have previously been shown to differentiate along the (skeletal) myogenic lineage. The potential for targeted induction along the cardiomyogenic lineage will be explored using co-culture techniques in conjunction with bioactive factors implicated in cardiogenic commitment and differentiation. 2) Explore the plasticity of hADCs after implantation into a normal myocardial milieu in a murine model. The microenvironment is known to significantly influence cell growth and differentiation. Therefore, the fate of hADCs after intramyocardial injection will be evaluated. 3) Explore the plasticity of hADCs after implantation into an infarcted myocardial milieu in vivo using a murine model. Signals released by damaged tissues have been shown to influence the growth, migration and differentiation of cells in vivo. This specific aim will determine whether intramyocardial injection of hADCs can reduce LV remodeling and improve cardiac function in a murine model of chronic myocardial infarction.

描述（由申请人提供）：再生干细胞疗法的前景是不可能实现临床翻译没有一个丰富的，容易获得的，无争议的细胞来源的鉴定。我们的实验室已经确定脂肪组织作为这样的候选细胞来源。来自人脂肪组织的细胞群体在体外显示多谱系发育可塑性，包括成脂、成骨、成软骨、成神经和成肌潜能。脂肪组织，比任何其他主要的成人组织，有可能使翻译的自体细胞为基础的范例，临床，因为它的丰富性，易于收获，吸引力，消耗性，和无争议的性质。该提案将在三种情况下专门探索人脂肪来源的细胞的心肌发生潜力：1）体外，2）在未损伤的心肌中，和3）在梗死心肌中。这将由一个多学科团队完成，该团队由临床医生、研究人员和工程师组成，涵盖整形外科、放射学、心脏生理学、细胞和分子生物学以及生物医学工程等领域。体内研究将采用由合作研究者在UVA建立的继发于再灌注心肌梗死（MI）的左心室重塑小鼠模型。使用该模型，将使用最先进的磁共振成像（MRI）结合先进的心肌标记技术，以连续的非侵入性方式评估MI后细胞移植对整体和局部心肌功能的影响。本提案的具体目的是：1）在体外环境中探索和表征人脂肪衍生细胞（hADC）的心肌发生潜力。这些细胞先前已显示出沿（骨骼）肌源性谱系沿着分化。将使用共培养技术结合与心源性定向和分化有关的生物活性因子来探索沿着心肌源性谱系进行靶向诱导的潜力。2)在小鼠模型中探索hADC植入正常心肌环境后的可塑性。已知微环境显著影响细胞生长和分化。因此，将评价心肌内注射后hADC的命运。3)使用小鼠模型探索hADC在体内植入梗死心肌环境后的可塑性。损伤组织释放的信号已被证明会影响体内细胞的生长、迁移和分化。这一特定目标将确定在慢性心肌梗死的鼠模型中心肌内注射hADC是否可以减少LV重构并改善心脏功能。