权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Using a Cardiac Microtissue System to Evaluate and Replicate Clinical Therapy Responses using Patient Cell-Derived Exosomes

使用心脏微组织系统评估和复制患者细胞衍生的外泌体的临床治疗反应

基本信息

批准号：
9924691
负责人：
Camila Hochman-Mendez
金额：
$ 20.38万
依托单位：
TEXAS HEART INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924691
关键词：
Action Potentials Allogenic Architecture Autologous Basement membrane Beds Biological Bone Marrow Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell Proliferation Cell Survival Cell Therapy Cell Transplantation Cell physiology Cells Characteristics Clinical Clinical Trials Clinical Trials Network Congestive Heart Failure Data Development Endothelial Cells Environment Exposure to Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Frequencies Future Genes Glucose Heart Human Hypoxia In Vitro Individual Infarction Injury Institutes Laboratories Lead Left Ventricular Ejection Fraction Link Mediator of activation protein Mesenchymal Stem Cells Modeling Molecular Myocardial Myocardial Infarction Myocardium National Heart, Lung, and Blood Institute Natural regeneration Organ Outcome Oxygen Consumption Patients Phenotype Physiological Placebos Play Process Property Proteins RNA Resistance Role Sampling Stress System Testing Texas Therapeutic Studies Tissue Engineering Vesicle base biobank cardiac regeneration cardiac repair cardiac tissue engineering cell behavior clinical effect design exosome experience functional improvement high throughput screening improved in vitro Model in vivo individual patient induced pluripotent stem cell injured innovation insight interest interstitial loss of function novel novel strategies paracrine patient response prevent regenerative repaired response stem cell differentiation stem cells success tissue repair

项目摘要

Summary Cell therapy for post-infarct cardiac repair has shown limited and mixed results, most likely due to patients' individual cell characteristics or to the infarct environment experienced by the transplanted cells. Identifying the potential molecular and cellular components that contribute to patient-specific responses and ways to minimize the environmental stress on transplanted cells may lead to the development of new strategies for cardiac repair. Additionally, numerous studies have shown that the effects of at least some cell-based therapies can be attributed primarily to secreted cellular factors that are packaged inside exosomes. These exosomes are considered critical mediators of intercellular information and play a direct role in injury-induced tissue repair processes in multiple physiological systems. Our group is particularly interested in the characterization of exosomes from cardiovascular disease patients who improved in a cell therapy study and in the utilization of these exosome cargos in the development of tissue-engineered cardiac patches for optimal functional myocardial repair. We are also interested in using our in vitro cardiac microtissue system as a testbed to evaluate patient cell-exosome interactions and associations with clinical trial responses. We will derive bone marrow mesenchymal stem cells (MSCs), MSC exosomes, and human induced pluripotent stem cells (hiPSCs) from healthy individuals and patients in the Cardiovascular Cell Therapy Research Network (CCTRN)-FOCUS clinical trial categorized as improvers at 6 months, [i.e., improved left ventricular ejection fraction, end-systolic volume and maximal oxygen consumption], or as non-improvers (declined in the 3 outcomes). Cardiac microtissues, containing cardiac cells derived from healthy control hiPSCs, cultured in native and infarct-like conditions will be treated with improvers' exosomes. Changes in microtissue function, cardiomyocyte maturation, cell survival and proliferation will be compared among improvers, placebo and non-improvers exosomes. Meanwhile, high throughput assays will be used to identify differences in the exosome cargos of the top 3 clinical improvers and non-improvers and correlated with in vitro responses. We expect that improver's exosomes will contain potent beneficial factors to enhance cell and microtissue maturation and function under infarct-like stress. Next, patient- specific microtissues containing hiPSC-derived cardiac cells generated from bone marrow of the top 3 improvers and non-improvers will be treated with autologous or allogenic (improver, non-improver or, healthy) exosomes under infarct-like conditions. By exposing patient-specific “infarcted” cardiac microtissues to autologous or allogeneic exosomes, we can evaluate patient-specific cell-exosome interactions in a controlled in vitro setting that mimics the clinical condition. Ultimately, these studies will provide new insights into cell-exosome interactions in an infarct as well as their relative potency and association with clinical trial responses, thus providing an innovative new approach to developing cardiac patches with superior regenerative properties.

总结