Derivation of Porcine iPS Cells and iPS Cell-Derived Cardiomyocytes

描述(由申请人提供)：本申请涉及广泛的挑战领域(11)再生医学和特定的挑战主题，11-HL-101：开发心血管、肺和血液疾病的基于细胞的疗法。患者特异性诱导多能干细胞(IPS)的获得为再生医学的未来应用开辟了新的途径。然而，在iPS细胞安全临床应用成为可能之前，在临床前的大动物模型中验证iPS细胞在体内的行为和命运是至关重要的。猪心在解剖学和生理学上比小动物模型更接近人类，因此可以作为评估和验证个体特异性iPS细胞治疗的极佳模型。在这项NIH挑战资助计划中，我们建议使用一种新型的非病毒微环载体从猪脂肪基质细胞中培养出猪iPS细胞。来自个体特异性猪iPS细胞的心肌细胞将接受自体心脏移植。然后，将用新的分子成像技术评估移植的个体特异性心肌细胞在体内的存活、增殖、分化和整合。总之，猪iPS细胞、iPS衍生物和自体移植模型应该为未来人类患者特异性iPS细胞疗法的临床翻译提供有价值的信息。 公共卫生相关性：个体特异性的猪iPS细胞和大型动物猪模型的结合为评估和验证人类个体特异性的iPS细胞疗法创造了一个极好的临床前模型。我们建议培养猪iPS细胞，并获得iPS细胞来源的心肌细胞，以利用新的分子成像技术评估自体移植的体内治疗效果。如果成功，这项研究将为未来针对患者的再生疗法治疗充血性心力衰竭和先天性心脏病等疾病的临床试验提供有价值的临床前信息。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (11) Regenerative Medicine and specific Challenge Topic, 11-HL-101: Develop cell-based therapies for cardiovascular, lung, and blood diseases. Derivation of patient-specific induced pluripotent stem (iPS) cells opens a new avenue for the future applications of regenerative medicine. However, it is critical to validate iPS cells' in vivo behavior and fate after autologous transplantation in pre-clinical large animal models before their safe clinical application becomes possible. The pig heart is anatomically and physiologically more similar than small animal models to human and therefore can serve as an excellent model for evaluating and validating individual-specific iPS cell-based therapies. In this NIH Challenge Grant proposal, we propose to generate porcine iPS cells from pig adipose stromal cells with a novel non-viral minicircle vector. Cardiomyocytes that are derived from individual-specific porcine iPS cells will undergo autologous cardiac transplantation. The in vivo survival, proliferation, differentiation, and integration of transplanted individual-specific cardiomyocytes will then be evaluated with novel molecular imaging techniques. Together, porcine iPS cells, iPS derivatives, and the autologous transplantation model should provide valuable information for future clinical translation of human patient-specific iPS cell therapies. PUBLIC HEALTH RELEVANCE: The combination of individual-specific porcine iPS cells and the large animal pig model creates an excellent pre-clinical model for evaluating and validating individual-specific iPS cell-based therapies in humans. We propose to generate porcine iPS cells and obtain iPS cell-derived heart muscle cells to assess the in vivo therapeutic effect of autologous transplantation using novel molecular imaging techniques. If successful, this study will provide valuable pre-clinical information for future clinical trials on patient-specific regenerative therapies for such diseases such as congestive heart failure and congenital heart conditions, etc.