Human Chemically induced Pluripotent Stem Cells (CiPSC) generated Cardiomyocytes

描述（由申请人提供）：通过诱导成人体细胞的直接重编程产生的人类干细胞，称为诱导多能干（iPS）细胞，为研究人类疾病特异性/个性化模型提供了“范式转变”机会，并为实际的自体细胞治疗、再生医学和预测毒理学应用提供了个性化的可再生细胞来源。该提案中概述的研究旨在探索CiPSC用于产生个性化心肌细胞的应用，这些心肌细胞可用于心血管疾病的建模，毒理学测试并最终用于心血管再生细胞治疗。我们建议使用一种新的稳健和有效的iPS方法，该方法采用小分子诱导剂的混合物，称为“化学诱导的多能干细胞（CiPSC）”，消除了对任何外源基因转导的需要（即其他人描述的iPS方法的主要障碍）。在该提议中，将通过使用用于从iPS和hESC体外衍生心肌细胞的完善程序衍生心肌细胞（CiPSC-CM）来证明该方法的可行性。获得这些CiPSC而没有对通常通过其他DNA载体诱导的iPS方法观察到的细胞和分子机制的任何异常和永久性修饰。我们的长期目标（II期及以后）是使用CiPSC-CM产生宿主相容的CM替代疗法，产生体外疾病特异性模型，并促进动物和人类模型系统中的体外治疗和毒性筛选。 公共卫生相关性：通过成人体细胞的诱导直接重编程产生的人类干细胞，称为诱导多能干（iPS）细胞，为研究人类疾病特异性/个性化模型提供了“范式转变”机会，并为实际的自体细胞疗法、再生医学和预测毒理学应用提供了个性化的可再生细胞来源。然而，使用iPS细胞作为开发这种患者和疾病特异性模型系统的工具的可能性充其量仍然具有挑战性，并且由于该领域的缺点，仍然存在明显的未满足的需求。该提案中概述的研究旨在探索化学诱导多能干细胞（CiPSC）用于生成个性化心肌细胞的应用，这些心肌细胞可用于心血管疾病建模，毒理学测试并最终用于心血管再生细胞治疗。CiPSC消除了对任何外源基因转导的需要，这是迄今为止由其他人描述的iPS方法的主要障碍。

DESCRIPTION (provided by applicant): Human stem cells generated by induced direct reprogramming of adult somatic cells, termed induced pluripotent stem (iPS) cells, offer "paradigm shifting" opportunities for studying human disease specific/ personalized models, and provide a personalized renewable source of cells for practical autologous cell therapies, regenerative medicine, and predictive toxicology applications. Studies outlined in this proposal are designed to explore application of CiPSC for the generation of personalized cardiomyocytes which can be used for modeling of cardiovascular diseases, toxicology testing and ultimately for cardiovascular regenerative cell therapy. We propose to use a novel robust and efficient iPS methodology which employs a cocktail of small molecule inducers, termed "Chemically induced Pluripotent Stem (CiPSC), eliminating the need for any exogenous gene transduction (i.e. a major impediment of iPS methodologies described by others). In this proposal, feasibility of this approach will be demonstrated via derivation of cardiomyocytes (CiPSC-CM) using well established procedures for in-vitro derivation of cardiomyocytes from iPS and hESC. These CiPSC are obtained without any abnormal and permanent modifications to the cellular and molecular machinery typically observed by other DNA vector induced iPS methodologies. Our long-term goals (Phase II and beyond) are to use CiPSC-CMs in generating host- compatible CM replacement therapy, producing in-vitro disease-specific model and facilitating in-vitro therapeutic and toxicity screen in animal and human model systems. PUBLIC HEALTH RELEVANCE: Human stem cells generated by induced direct reprogramming of adult somatic cells, termed induced pluripotent stem (iPS) cells, offer "paradigm shifting" opportunities for studying human disease specific/ personalized models, and provide a personalized renewable source of cells for practical autologous cell therapies, regenerative medicine, and predictive toxicology applications. The possibility of using iPS cells as a tool for development of such patient and disease specific model systems, however, remains at best challenging and stills a clear unmet need due to the shortcomings in this field. Studies outlined in this proposal are designed to explore application of Chemically induced Pluripotent Stem Cells (CiPSC) for the generation of personalized cardiomyocytes which can be used for modeling of cardiovascular diseases, toxicology testing and ultimately for cardiovascular regenerative cell therapy. CiPSC eliminates the need for any exogenous gene transduction, which is a major impediment of iPS methodologies described to date by others.