Epigenomic Memory of iPSC-Derived Endothelial Cells for Cardiovascular Diseases

iPSC 衍生的内皮细胞对心血管疾病的表观基因组记忆

• 批准号: 8199431
• 负责人: Shin Lin
• 金额: $ 5.68万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-20 至 2014-07-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8199431
• 关键词: Affect; Animals; Behavior; Bioinformatics; Biological Process; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cell Line; Cell Transplants; Cells; Clinical; Derivation procedure; Doctor of Philosophy; Embryo; Endothelial Cells; Epigenetic Process; Ethics; Fibroblasts; Generations; Genetic; Genomics; Goals; Histocompatibility Testing; Human; Immune; In Vitro; Intervention; Lead; Magnetic Resonance Imaging; Medicine; Memory; Mentors; Modeling; Molecular; Molecular Biology; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Patients; Population; Preparation; Radiology Specialty; Regenerative Medicine; Research Proposals; Resolution; Safety; Science; Somatic Cell; Source; Stem cells; System; Techniques; Technology; Therapeutic; Time; Tissues; Training; base; cell preparation; clinical practice; epigenomics; human embryonic stem cell; induced pluripotent stem cell; infancy; molecular imaging; multidisciplinary; novel; professor; research study; statistics; stem cell differentiation

DESCRIPTION (provided by applicant): Induced pluripotent stem cells (iPSCs) are a novel source for cardiovascular regenerative medicine. Because iPSCs are derived from the tissues of recipient patients, they obviate two major problems in the field of human embryonic stem cells (hESCs), namely immune rejection and the political/ethical concerns regarding the destruction of embryos. However, at present the field is in its infancy, and issues surrounding the efficiency, safety, and efficacy of iPSC-based derivatives require resolution before reduction to clinical practice occurs. This multi-disciplinary project will investigate the epigenomics of iPSC-derived endothelial cells (iPSC-ECs) for use in a murine myocardial infarction model. First, endothelial cells and fibroblasts will be de-differentiated into iPSCs. These two lines, as well as hESCs, will then be differentiating into endothelial cells. The stem cells, their tissues of origin (for the two iPSCs), and their endothelial derived tissues will be subjected to second-generation sequencing to determine their epigenomic states. Finally, the three stem cell-derived endothelial cell lines will be injected into a murine myocardial infarction system. Their effects on myocardial function will be observed over time. These experiments are anticipated to reveal the epigenomic features underlying more efficient somatic cell reprogramming, more robust stem cell differentiation, and greater therapeutic capacity for myocardial ischemia. These studies should pave the way to identifying molecular interventions which can be integrated into iPSC-EC preparation, so that eventually, these stem cell derivatives may be effective in the clinical setting for cardiovascular disease patients PUBLIC HEALTH RELEVANCE: Studying the epigenomics of stem-cell reprogramming and differentiation should allow for greater efficiency in their preparation. Tracking their subsequent behavior in a myocardial ischemia model will lead to molecular manipulations of the epigenome to make them more beneficial to patients.

描述（由申请人提供）：诱导多能干细胞（iPSC）是心血管再生医学的新来源。由于iPSC来源于受体患者的组织，因此它们克服了人类胚胎干细胞（hESC）领域的两个主要问题，即免疫排斥和关于胚胎破坏的政治/伦理问题。然而，目前该领域还处于起步阶段，围绕iPSC衍生物的效率，安全性和有效性的问题需要在减少临床实践之前解决。 这个多学科项目将研究iPSC衍生的内皮细胞（iPSC-ECs）的表观基因组学，用于小鼠心肌梗死模型。首先，内皮细胞和成纤维细胞将去分化为iPSC。这两个细胞系以及hESC将分化为内皮细胞。干细胞、其来源组织（对于两种iPSC）和其内皮衍生组织将经受第二代测序以确定其表观基因组状态。最后，将三种干细胞衍生的内皮细胞系注射到鼠心肌梗死系统中。将随时间观察其对心肌功能的影响。这些实验有望揭示更有效的体细胞重编程、更稳健的干细胞分化和更大的心肌缺血治疗能力的表观基因组特征。这些研究应该为确定可以整合到iPSC-EC制剂中的分子干预铺平道路，以便最终这些干细胞衍生物在心血管疾病患者的临床环境中有效 公共卫生相关性：研究干细胞重编程和分化的表观基因组学应该可以提高制备干细胞的效率。在心肌缺血模型中追踪它们随后的行为将导致表观基因组的分子操作，使它们对患者更有益。