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: 10229460
• 负责人: Ke Cheng
• 金额: $ 75.99万
• 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/10229460
• 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; donor stem cell; extracellular vesicles; heart function; immunogenicity; implantation; improved; innovation; mouse model; porcine model; preservation; regenerative; release factor; repair model; 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 干细胞治疗是再生医学中一种很有前途的策略。然而， 细胞在使用前需要小心地保存和处理。此外，细胞移植 具有一定的免疫原性和/或致瘤性风险。无细胞和非细胞的发展 来自干细胞的活疗法有可能彻底改变目前的再生 医学实践越来越多的证据表明，干细胞发挥其有益的作用， 主要是通过分泌促再生因子。在此基础上，我们制作了“合成 心脏干细胞（synCSC）”通过将心脏干细胞分泌的因子包封在可生物降解的 聚合物嵌段。在心肌梗死（MI）的小鼠模型中，心肌内注射synCSC 导致存活心肌的保存和心脏功能的增强，类似于真实的CSC 通过永久性血管结扎治疗免疫缺陷小鼠心肌梗死。尽管 成功的概念验证，一个巨大的挑战是有效地将合成细胞输送到心脏。 目前的建议是一个逻辑的进展，从我们以前的工作。我们会在这里 开发和测试一种新实体：通过嵌入形成的人工心脏贴片（artCP） synCSC转化为脱细胞的心肌细胞外基质（ECM）。我们的研究将从 在小型/大型动物中，将先前的啮齿动物急性MI模型转化为慢性心力衰竭模型。的 总体假设是artCP可以进一步改善synCSC治疗在大鼠中的功效， 慢性心脏损伤的猪目的1制备artCP并测定其体外效价。目标二是 确定artCP治疗慢性梗塞大鼠模型的安全性和有效性。目标3：翻译 将这些发现转化为临床相关的晚期心肌病猪模型。我们的研究将形成 基于干细胞因子的创新和“现成”疗法的基础， 心肌ECM我们的方法的无细胞性质更容易转化为临床。 虽然这个特殊的拨款申请的目标是心脏和心脏干细胞， 代表了一种平台技术，可以应用于创建多种类型的合成 干细胞和ECM用于修复各种其他器官。