Smarter exosomes derived from engineered MSCs promote neo-vascularization

源自工程化 MSC 的更智能的外泌体可促进新血管形成

基本信息

批准号：
10078974
负责人：
Min Liu
金额：
$ 50.5万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10078974
关键词：
Adverse effects Angiogenesis Inhibitors Animals Caliber Cardiac Cardiac Myocytes Cardiovascular Diseases Cause of Death Cell Therapy Cell membrane Cells Data Dose Effectiveness Encapsulated Endothelial Cells Engineering Extracellular Space Family Future Goals Heart Immune In Vitro Injections Intravenous Liposomes Mediating Mesenchymal Stem Cells Modality Modeling Morphogenesis Myocardial Myocardial Infarction Myocardial Ischemia Myocardial tissue Myocardium Natural regeneration Outcome Parents Pathway interactions Patients Physiological Pilot Projects Play Pre-Clinical Model Property Proteins Publishing Recovery Reporting Risk Role Safety Signal Pathway Solid Stress THBS1 gene Technology Testing Therapeutic Effect Thrombospondin 1 Time Transfection Translational Research Validation Vascularization Vesicle angiogenesis base blood vessel development cardiac regeneration cardiac repair cardiovascular health clinical application clinical implementation compare effectiveness effective therapy exosome experimental study extracellular vesicles genetic manipulation genome editing heart damage heart function heart preservation improved in vivo injured innovation intravenous administration intravenous injection ischemic injury loss of function myocardial injury nanoparticle neovascularization overexpression paracrine preconditioning repaired response stem cell exosomes stem cell survival stem cell therapy stem cells success therapy outcome tissue regeneration tissue repair transcription factor transdifferentiation vector vesicular release

项目摘要

Project Summary/Abstract Mesenchymal stem cell (MSC) therapy has shown tremendous promise for enabling heart tissue repair after ischemic injury. The therapeutic effects of stem cells are mediated by paracrine factors. Several studies illustrate that exosomes (EXO) derived from stem cells play a critical role in stem cell mediated therapy of ischemic myocardium via increasing angiogenesis. From the translational perspective, EXO have greater salutary therapeutic effects than whole cells: EXO have fewer potential adverse effects, less immune rejection, are more amenable to manipulation, and EXO cargo can be modified by preconditioning or genetic manipulation. GATA- 4, a cardiac transcription factor, promotes cardiac morphogenesis, extends cardiomyocyte (CM) survival and preserves cardiac function via regulating various bioactive molecules and activating cardiac protective miRs. Our published data indicate that MSC overexpressing GATA-4 (MSCGATA-4) increase MSC survival, protect native CM and promote angiogenesis, compared to vector-transfect MSC (MSCnull). EXO derived from EXO derived from GATA-4 overexpressing GATA-4 (ExoGATA-4) are more efficient than EXO from vector-transfected MSC (Exonull) in protecting CM from ischemic injury. In our pilot study, ExoGATA-4 are enriched with pro-angiogenic miRs, which regulate vascularization. ExoGATA-4 downregulate the expression of thrombospondin 1, a well-known endogenous inhibitor of neovascularization. The overarching goal of this project is to exploit effectiveness of GATA-4 conferred EXO than the ordinary EXO in repairable effects of ExoGATA-4. Our central hypothesis is that the ExoGATA-4 are enriched with pro-angiogenic miRs and proteins that are transferred into recipient cells and active multiple signaling pathways, leading to angiogenesis and cardiac repair. Three Specific Aims are proposed: Aim 1, to determine the role of miRs carried by EXO in response to GATA-4 transfection. Aim 2, to demonstrate if the transferred bioactive molecules play a critical role in ExoGATA-4 mediated angiogenesis. Aim 3, to test the hypothesis that EXO derived from GATA-4 overexpressing MSCs are more effective than that from vector-transfected MSCs in promoting angiogenesis and myocardial regeneration. The proposed studies are innovative because no previous study has systematically examined the effectiveness of ExoGATA-4, with particular focus on the efficacy of EXO mediated angiogenesis and ischemic heart repair following systemic administration. Intravenous injection offers the advantage of enabling repeated treatments without the stress of repeated intramyocardial injections. The proposed study is highly significant because it will evaluate the concept that the effectiveness of cellular therapy can be reproduced by cell-free EXO and will explore this new modality for future clinical application by intravenous administration. This project will be the first systematic effort aimed at developing a completely new strategy in use of EXO administration in lieu of cells, which would revolutionize cell therapy. The outcome will offer a transformative validation and guide translational research and putative therapies based on enhanced angiogenic properties of EXO from genome-edited MSCs. 1

项目摘要/摘要间充质干细胞（MSC）疗法已显示出巨大的希望缺血性损伤。干细胞的治疗作用是由旁分泌因子介导的。几项研究说明了源自干细胞的外泌体（EXO）在干细胞介导的缺血疗法中起关键作用心肌通过增加血管生成。从转化的角度来看，EXO具有更大的有益比整个细胞的治疗作用：EXO具有更少的潜在不良影响，免疫排斥较少，更多的是可以通过预处理或遗传操作来修改操纵和EXO货物。 gata- 4，一种心脏转录因子，促进心脏形态发生，扩展心肌细胞（CM）生存和通过调节各种生物活性分子并激活心脏保护miR来保存心脏功能。我们已发布的数据表明，MSC过表达GATA-4（MSCGATA-4）增加了MSC的生存，保护天然与载体传输MSC（MSCNULL）相比，CM并促进血管生成。源自EXO衍生的EXO 从GATA-4过表达GATA-4（exogata-4）比从矢量转染的MSC中更有效（外部）保护CM免受缺血性损伤。在我们的试点研究中，Exogata-4富含促血管生成 miR，调节血管化。 exogata-4下调血小板传播1的表达，一个知名的内源性抑制剂新血管形成。该项目的总体目标是利用 GATA-4在Exogata-4的可修复作用中赋予EXO比普通EXO。我们的中心假设是 Exogata-4富含促血管生成的miR和蛋白质，这些miR和蛋白质被转移到受体细胞中，主动多重信号通路，导致血管生成和心脏修复。三个具体目标是提出的：目标1，确定EXO响应GATA-4转染的MIR的作用。目标2，to 证明转移的生物活性分子是否在exogata-4介导的血管生成中起关键作用。目的 3，为了检验以下假设：从GATA-4过表达MSC的EXO比来自载体转染的MSC在促进血管生成和心肌再生方面。拟议的研究是创新性是因为没有以前的研究系统地检查了Exogata-4的有效性，特别关注Exo介导的血管生成和缺血性心脏修复的功效行政。静脉注射提供了实现重复治疗而没有压力的优势重复的心膜内注射。拟议的研究非常重要，因为它将评估细胞疗法的有效性可以通过无细胞EXO再现，并将探索这一新的概念静脉内给药的未来临床应用方式。该项目将是第一个系统的努力旨在制定一种全新的策略，用于使用EXO给药以代替细胞，这将革新细胞疗法。结果将提供变革性验证并指导转化研究，并基于基因组编辑MSC的EXO增强的血管生成特性的推定疗法。 1