Reprogramming of endothelial cells for improved cardiomyogenicity in vivo

内皮细胞重编程以改善体内心肌原性

• 批准号: 8127267
• 负责人: MELISSA ANN THAL
• 金额: $ 4.84万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127267
• 关键词: Acute myocardial infarction; American; Animal Model; Autologous; Azacitidine; Back; Blood Vessels; Bone Marrow; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Differentiation process; Cell Therapy; Cells; Chemical Modifier; Chemicals; Chronic; Clinic; Clinical; Coronary heart disease; DNA Methylation; Data; Development; Endothelial Cells; Epigenetic Process; Gene Expression; Genes; Goals; HDAC1 gene; Health; Heart; Heart Diseases; Heart failure; Histone Acetylation; Histones; In Vitro; Left Ventricular Function; Life; Mediating; Mediator of activation protein; Mesenchymal Stem Cells; Mesoderm; Methylation; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Myocardium; Natural regeneration; Patients; Phenotype; Plastics; Property; Quality of life; Regenerative Medicine; Role; Smooth Muscle Myocytes; Somatic Cell; Stem cells; Testing; Therapeutic; Tissues; Transplantation; Treatment Efficacy; Trichostatin A; United States; Valproic Acid; Vascular Endothelial Cell; Vascularization; Wound Healing; cell type; chromatin remodeling; embryonic stem cell; histone modification; improved; in vivo; inhibitor/antagonist; injured; interest; mortality; multipotent cell; myogenesis; neovasculature; novel; paracrine; progenitor; promoter; regenerative; repaired; research study; small molecule

DESCRIPTION (provided by applicant): Heart failure due to heart disease is a major health concern and a leading cause of mortality worldwide. Despite improvements in treatment options, repair of damaged myocardial tissue is still a central therapeutic challenge in cardiovascular regenerative medicine. Currently, bone marrow derived endothelial progenitor cells (BM-EPCs) are being used clinically to improve vascularization in patients with ischemic heart disease. The therapeutic benefits of BM-EPC therapy in animal models have been attributed to paracrine factors-mediated vascular repair without myogenesis and/or myocardial regeneration. Therefore, the long-term goal of this proposal is to improve the cardiomyogenic properties of an existing autologous cell therapy approved for the clinic. This proposal focuses on epigenetically modifying endothelial cells to create multipotent cells capable of repairing cardiac tissue after an acute myocardial infarction. Endothelial cells and cardiomyocytes both differentiate from a common progenitor in the mesoderm, suggesting that reprogramming endothelial cells back to that early state in mesoderm development could recapitulate their cardiomyogenic potential. Epigenetic reprogramming using chemical modifiers of DNA methylation (5-Azacytidine) and histone acetylation (valproic acid) have been shown to change the trans-differentiation capabilities of a given cell. For instance, mesenchymal stem cells (MSC) treated with 5'Azacytidine have an increase in cardiomyocyte differentiation and they improve cardiac function upon transplantation compared to control MSCs. In our preliminary experiments we find: a.) treatment of endothelial progenitor cells with epigenetic modifiers induces the expression of non-endothelial specific genes, while b.) endothelial-specific gene expression is maintained, c.) reprogrammed cells can be re-differentiated into cardiomyocytes under proper in vitro conditions and d.) epigenetically modified endothelial progenitor cells are therapeutically superior in the myocardial infarction model to non-treated cells. Therefore, we hypothesize that epigenetic modifying agents can reprogram endothelial cells to a multipotent state, capable of regenerating and/or repairing injured myocardium in vivo by differentiating into both cardiomyocytes and endothelial cells. PUBLIC HEALTH RELEVANCE: Heart disease is a leading cause of morbidity and mortality amongst Americans. Our studies, if successful, will generate a novel set of well-controlled experimental evidence supporting the increased potential for regeneration of the heart when endothelial progenitor cells are treated with 5'Azacytidine, Trichostatin A and valproic acid. Most importantly, our results may significantly improve an existing cellular therapy and improve the lives of the over 16 million patients in the United States living with coronary heart disease.

描述（由申请人提供）：心脏病引起的心力衰竭是一个主要的健康问题，也是全世界死亡的主要原因。尽管治疗方案有所改进，受损心肌组织的修复仍然是心血管再生医学的主要治疗挑战。目前，骨髓来源的内皮祖细胞（BM-EPC）正在临床上用于改善缺血性心脏病患者的血管化。 BM-EPC 疗法在动物模型中的治疗效果归因于旁分泌因子介导的血管修复，无需肌生成和/或心肌再生。因此，该提案的长期目标是改善临床批准的现有自体细胞疗法的心肌生成特性。 该提案的重点是对内皮细胞进行表观遗传修饰，以产生能够在急性心肌梗死后修复心脏组织的多能细胞。内皮细胞和心肌细胞均从中胚层中的共同祖细胞分化而来，这表明将内皮细胞重编程回中胚层发育的早期状态可以重现其心肌生成潜力。使用 DNA 甲基化（5-氮杂胞苷）和组蛋白乙酰化（丙戊酸）的化学修饰剂进行表观遗传重编程已被证明可以改变给定细胞的转分化能力。例如，与对照 MSC 相比，用 5'氮胞苷处理的间充质干细胞 (MSC) 可以增加心肌细胞的分化，并且在移植后改善心脏功能。在我们的初步实验中，我们发现：a.）用表观遗传修饰剂处理内皮祖细胞会诱导非内皮特异性基因的表达，而b.）内皮特异性基因的表达得以维持，c.）重编程的细胞可以重新分化在适当的体外条件下进入心肌细胞，并且d.)表观遗传修饰的内皮祖细胞在心肌梗塞模型中的治疗效果优于未处理的细胞。因此，我们假设表观遗传修饰剂可以将内皮细胞重编程为多能状态，能够通过分化为心肌细胞和内皮细胞来再生和/或修复体内受损的心肌。 公共卫生相关性：心脏病是美国人发病和死亡的主要原因。我们的研究如果成功，将产生一组新的控制良好的实验证据，支持当内皮祖细胞用 5'氮胞苷、曲古抑菌素 A 和丙戊酸处理时，心脏再生的潜力增加。最重要的是，我们的结果可能会显着改善现有的细胞疗法，并改善美国超过 1600 万冠心病患者的生活。