Cardiac Patches Loaded with Stem Cell Factors to Treat Heart Failure

项目总结 干细胞疗法代表了再生医学中一种很有前途的策略。然而，现场直播 细胞在使用前需要仔细保存和处理。此外，细胞移植 具有一定的免疫原性和/或致瘤性风险。无细胞和非细胞生物材料的发展 干细胞衍生的生命疗法有可能彻底改变目前的再生能力。 行医。越来越多的证据表明干细胞发挥了有益的作用 主要通过分泌促再生因子来实现。在此基础上，我们制造了“合成的 心脏干细胞(SynCSCs)将心脏干细胞分泌的因子包裹在可生物降解的 聚合物块。在心肌梗死(MI)小鼠模型中，心肌内注射SyncSCs 导致存活心肌的保存和心脏功能的增强，类似于真正的CSC 永久性血管结扎法治疗免疫缺陷小鼠心肌梗死。尽管 成功的概念证明，一个巨大的挑战是有效地将合成细胞输送到心脏。 本提案是我们以前工作的一个逻辑进展。我们会在这里 开发和测试一种新的实体：通过嵌入形成的人工心脏补片(ArtCP) 将干细胞合成去细胞的心肌细胞外基质(ECM)。我们的研究将从 以前的啮齿动物急性心肌梗死模型到慢性心力衰竭模型，在小动物和大动物中都是如此。这个 最重要的假说是ArtCPs可以进一步提高大鼠SyncsC治疗的疗效和 患有慢性心脏损伤的猪。目的1制备ARTCPs并测定其体外效力。目标2是 探讨artCP治疗慢性脑梗塞大鼠模型的安全性和有效性。目标3是翻译 这一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 以干细胞因子为基础的创新的现成疗法的基础 心肌细胞外基质。我们方法的无细胞本质更容易移植到临床上。 虽然这一特别的拨款申请针对的是心脏和心脏干细胞，但我们的方法 表示可应用于创建多种类型的合成的平台技术 干细胞和细胞外基质，用于修复其他各种器官。

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.