Integration Free IPS Cells-Derived Progenitors for Cardiac Regeneration

用于心脏再生的免整合 IPS 细胞衍生祖细胞

• 批准号: 9226014
• 负责人: Jalees Rehman
• 金额: $ 74.91万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9226014
• 关键词: Animals; Apoptosis; Autologous; Behavior; Biology; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Line; Cell Lineage; Cell Therapy; Cell surface; Cells; Characteristics; Chromatin; Cicatrix; DNA; Data; Development; Engraftment; Enzymes; Epigenetic Process; Experimental Animal Model; Family suidae; Fibroblasts; Fibrosis; Generations; Genetic; Genome; Goals; Health; Hearing problem; Heart; Heart Diseases; Human; Human Cell Line; Hypoxia; Infarction; Ischemic Preconditioning; Methods; Modeling; Molecular Biology; Mus; Muscle Cells; Myoblasts; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Nature; Patients; Physiology; Pluripotent Stem Cells; Population; Process; Proteins; Recombinants; Research; Risk; Signal Transduction; Skeletal Muscle; Skeletal Myoblasts; Source; Stem cells; Techniques; Testing; Therapeutic; Tissues; Transferase; Transplantation; Ultrasonography; Up-Regulation; Vascular Endothelial Growth Factors; Viral; Viral Vector; attenuation; base; cardiac regeneration; design; exosome; experience; functional outcomes; heart function; human pluripotent stem cell; improved; in vivo; induced pluripotent stem cell; inhibitor/antagonist; innovation; interdisciplinary approach; mouse model; pluripotency; pre-clinical; preconditioning; progenitor; public health relevance; regenerative therapy; repaired; small molecule; stem; stem cell therapy; transcription factor; tumor; vector-induced

DESCRIPTION (provided by applicant): The generation of induced pluripotent stem (iPS) cells is an innovative approach for generating autologous pluripotent stem cell lines for individualized cell therapy. Our research will use human skeletal muscle derived myoblasts rather than terminally differentiated fibroblasts for non-viral generation of iPS and their differentiation int cardiac progenitor cells. The hypothesis is that skeletal myoblasts (SMs) are superior candidates for induction to pluripotent state with fewer factors either alone or in combination with treatment with small molecules. Thus iPS derived cardiac progenitors may be readily generated with the use of cardiogenic small molecules, purified to generate off shelf universal cardiac cells. The direct generation of progenitors from iPS cells with specific small molecule may be a major current paradigm shift in stem cell therapy. We further propose that use of iPS derived cardiovascular progenitors will allow successful regeneration of infarcted myocardium without the risk of tumorgenecity. The hypotheses will be tested in the following specific Aims. Specific Aim-1will generate iPS cells from human SMs using small molecules; Specific Aim-2 will focus on developing strategies to direct iPS cells to cardiac and vascular progenitors; Specific Aim-3 will exploit the power of Ischemic preconditioning signaling in regulating survival and engraftment of iPS -progenitors in the ischemic tissue for effective regeneration; Specific Aim 4 will test that transplantation of iPS - progenitors and preconditioned progenitors effectivel regenerates infarcted myocardium and reverses fibrosis in murine and pre-clinical porcine heart models. The end points of the in vivo studies will be reversal of fibrosis through myoangiogenic differentiation of the engrafted progenitor cells, functional integration of developing cardiac myocytes into the host heart, attenuation of infarct size and the functional benefits in terms of improved global heart function. These studies will involve multidisciplinary approach which will employ state of the art molecular biology, histochemical and immunohistochemical techniques and well integrative physiology involving well established experimental animal model, and transthoracic ultrasonography for animal heart function. These studies are expected to facilitate robust cardiac differentiation and cardiomyocyte purification resulting in generation of unlimited number of cardiac progenitor cells from SM-iPS for restoring damaged myocardium without the risk of tumor formation.

描述（由申请人提供）：诱导多能干（iPS）细胞的产生是一种产生用于个体化细胞治疗的自体多能干细胞系的创新方法。我们的研究将使用人类骨骼肌来源的成肌细胞而不是终末分化的成纤维细胞来非病毒产生 iPS 及其向心脏祖细胞的分化。该假设认为，骨骼肌成肌细胞（SM）是单独或与小分子治疗相结合的较少因素诱导多能状态的最佳候选者。因此，使用心原性小分子可以容易地产生 iPS 衍生的心脏祖细胞，并纯化以产生现成的通用心脏细胞。从具有特定小分子的 iPS 细胞直接产生祖细胞可能是当前干细胞治疗的重大范式转变。我们进一步提出，使用 iPS 衍生的心血管祖细胞将允许梗塞心肌成功再生，而不会产生肿瘤风险。这些假设将在以下具体目标中得到检验。具体的 Aim-1 将使用小分子从人类 SM 中产生 iPS 细胞；具体的Aim-2将重点开发将iPS细胞引导至心脏和血管祖细胞的策略；具体的 Aim-3 将利用缺血预处理信号的力量来调节缺血组织中 iPS 祖细胞的存活和植入，从而实现有效再生；具体目标 4 将测试 iPS（祖细胞和预处理祖细胞）的移植能否有效地再生梗塞心肌并逆转小鼠和临床前猪心脏模型中的纤维化。体内研究的终点将是通过移植祖细胞的肌血管生成分化逆转纤维化、发育中的心肌细胞与宿主心脏的功能整合、梗塞面积的减小以及改善整体心脏功能方面的功能益处。这些研究将涉及多学科方法，将采用最先进的分子生物学、组织化学和免疫组织化学技术以及涉及完善的实验动物模型的综合生理学，以及用于动物心脏功能的经胸超声检查。这些研究预计将促进强健的心脏分化和心肌细胞纯化，从而从 SM-iPS 中产生无限数量的心脏祖细胞，以恢复受损的心肌，而没有形成肿瘤的风险。