Cardiac Patches Loaded with Stem Cell Factors to Treat Heart Failure

含有干细胞因子的心脏贴片可治疗心力衰竭

• 批准号: 10005456
• 负责人: Ke Cheng
• 金额: $ 60.79万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005456
• 关键词: Acute; Acute myocardial infarction; Anatomy; Animal Model; Animals; Applications Grants; Biological; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cause of Death; Cell Line; Cell Therapy; Cell Transplantation; Cells; Chronic; Clinic; Clinical; Clinical Research; Congestive Heart Failure; Control Groups; Cues; Degenerative Disorder; Development; Disease Progression; Disease model; Encapsulated; Endothelial Cells; Epicardium; Extracellular Matrix; Family suidae; Fibroblasts; Foundations; Future; Heart; Heart Diseases; Heart Injuries; Heart failure; Human; Immunologic Deficiency Syndromes; In Vitro; Infarction; Injections; Ischemia; Ligation; Logic; Membrane; Modeling; Mus; Myocardial; Myocardial Infarction; Myocardium; Nature; Operative Surgical Procedures; Organ; Patients; Procedures; Process; Proteins; Rattus; Regenerative Medicine; Reperfusion Injury; Reperfusion Therapy; Risk; Rodent; Safety; Standardization; Stem Cell Factor; Structure; Technology; Testing; Therapeutic; Tissues; Translating; Transplantation; Tumorigenicity; Work; adult stem cell; base; biodegradable polymer; cardiac regeneration; cardiac repair; clinical translation; clinically relevant; cytotoxicity; disability; extracellular vesicles; heart function; immunogenicity; implantation; improved; innovation; mouse model; preservation; regenerative; release factor; repaired; stem cell therapy; stem cells

PROJECT SUMMARY Stem cell therapy represents a promising strategy in regenerative medicine. However, live cells need to be carefully preserved and processed before usage. In addition, cell transplantation carries certain immunogenicity and/or tumorigenicity risks. The development of cell-free and non- living therapeutics derived from stem cells has the potential to revolutionize current regenerative medicine practice. Mounting lines of evidences indicate that stem cells exert their beneficial effects mainly through the secretion of pro-regenerative factors. Based on this, we fabricated “synthetic cardiac stem cells (synCSCs)” by encapsulating cardiac stem cell-secreted factors in a biodegradable polymer block. In a mouse model of myocardial infarction (MI), intramyocardial injection of synCSCs led to preservation of viable myocardium and augmentation of cardiac functions similar to real CSC therapy in immunodeficiency mice with myocardial infarction by permanent vessel ligation. Despite the successful proof of concept, a big challenge is the effective delivery of synthetic cells to the heart. The present proposal represents a logic progression from our previous work. Here we will be developing and testing a new entity: an artificial cardiac patch (artCP) formed by embedding synCSCs into decellularized myocardial extracellular matrix (ECM). Our studies will extend from the previous rodent acute MI model to a chronic heart failure model in both small/large animals. The overarching hypothesis is that artCPs can further improve the efficacy of synCSC therapy in rats and pigs with chronic heart injury. Aim 1 is to fabricate artCPs and determine in vitro potency. Aim 2 is to demine the safety and efficacy of artCP therapy in a rat model of chronic infarct. Aim 3 is to translate the findings into a clinically relevant porcine model of advanced cardiomyopathy. Our study will form the foundation for an innovative and “off the shelf” therapy based on stem cell factors and myocardium ECM. The cell-free nature of our approach is more readily translatable to the clinic. Although this particular grant application targets the heart and cardiac stem cells, our approach represents a platform technology that can be applied to the creation of multiple types of synthetic stem cell and ECMs for the repair of various other organs.

项目摘要 干细胞疗法代表了再生医学中的一种有希望的策略。但是，活着 在使用之前，需要仔细保存和处理细胞。另外，细胞移植 具有某些免疫原性和/或肿瘤性风险。无细胞和非细胞的发展 从干细胞中得出的生活疗法有可能彻底改变当前的再生 医学实践。证据的安装线表明干细胞发挥其有益作用 主要通过促进因素的分泌。基于此，我们制造了“合成 心脏干细胞（SyncScs）”通过将心脏干细胞分泌因子封装在可生物降解中 聚合物块。在心肌梗死（MI）的小鼠模型中，心脏内注射SyncSCS 导致保存可行的心肌和类似于实际CSC的心脏功能的增强 通过永久血管结扎的心肌梗塞在免疫缺陷小鼠中进行治疗。尽管 成功的概念证明，一个巨大的挑战是合成细胞向心脏的有效传递。 本提案代表了我们以前的工作的逻辑发展。我们将在这里 开发和测试一个新实体：通过嵌入形成的人造心脏贴片（ARTCP） SyncScs成脱细胞心肌外基质（ECM）。我们的研究将从 以前的啮齿动物急性MI模型是小动物/大型动物的慢性心力衰竭模型。这 总体假设是ARTCP可以进一步提高大鼠同步治疗的效率 患有慢性心脏损伤的猪。目标1是制造ARTCP并确定体外效力。目标2是 恶魔在慢性梗塞大鼠模型中ARTCP治疗的安全性和效率。目标3是翻译 这些发现成为晚期心肌病的临床相关猪模型。我们的研究将形成 基于干细胞因素和 心肌ECM。我们方法的无细胞性质更容易翻译成诊所。 尽管此特定的赠款应用针对心脏和心脏干细胞，但我们的方法 代表一种可以应用于多种合成类型的平台技术 干细胞和ECM，用于修复其他各种器官。