MYOCARDIAL PLASTICITY OF HUMAN FAT-DERIVED STEM CELLS

人类脂肪干细胞的心肌可塑性

• 批准号: 6570206
• 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
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6570206
• 关键词: adipocytes; adipose tissue; cell differentiation; cell growth regulation; cell migration; cell population study; clinical research; disease /disorder model; heart function; human tissue; laboratory mouse; mixed tissue /cell culture; myocardial infarction; myocardium; nonhuman therapy evaluation; reperfusion; stem cell transplantation; stem cells; tissue /cell culture

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)： 如果没有确定丰富、容易获得、无争议的细胞来源，再生性干细胞疗法的前景不太可能实现临床移植。我们的实验室已经确定脂肪组织就是这样一个候选细胞来源。人脂肪组织来源的细胞在体外表现出多谱系发育可塑性，包括成脂、成骨、成软骨、神经成骨和肌成肌的潜能。脂肪组织比任何其他原生人类成人组织更有可能将基于细胞的自体范例转化到临床上，因为它的丰富性、易获得性、吸引力、可消耗性和无争议的性质。这项建议将在三个方面专门探讨人类脂肪来源细胞的心肌生成潜力：1)体外，2)在未损伤的心肌中，以及3)在梗死心肌中。这将由一个由临床医生、研究人员和工程师组成的多学科团队完成，该团队涵盖整形外科、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。体内研究将采用小鼠左室重构的模型，继发于再灌注性心肌梗死(MI)，该模型已经由联合研究员在UVA建立。使用这一模型，将使用最先进的磁共振成像(MRI)和先进的心肌标记技术，以连续、非侵入性的方式评估细胞移植对心肌梗死后整体和局部心肌功能的影响。这项建议的具体目的是：1)探索和表征体外培养的人脂肪来源细胞(HADC)的心肌细胞分化潜能。这些细胞以前已经被证明沿着(骨骼)肌源性谱系分化。我们将利用共培养技术，结合与生心肌承诺和分化有关的生物活性因子，探索沿着生心肌谱系进行靶向诱导的可能性。2)建立小鼠心肌移植模型，探讨hADC植入正常心肌环境后的可塑性。众所周知，微环境显著影响细胞的生长和分化。因此，hADC在心肌内注射后的命运将被评估。3)建立小鼠心肌梗死模型，探讨hADC植入心肌梗死后的可塑性。损伤组织释放的信号已被证明影响体内细胞的生长、迁移和分化。这一特定的目的将决定心肌内注射hADC是否可以减少慢性心肌梗死小鼠模型的左室重构和改善心功能。