Characterization of the Cardiac Progenitor Cell Exosomes for Optimal Therapeutics

心脏祖细胞外泌体的表征以实现最佳治疗

• 批准号: 10467907
• 负责人: Sunjay Kaushal
• 金额: $ 68.61万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10467907
• 关键词: Adult; Animals; Antibodies; Apoptosis; Attenuated; Biogenesis; Cardiac; Cardiac Myocytes; Cell Survival; Cells; Clinical Trials; Complex; Congenital Heart Defects; Data; Enterobacteria phage P1 Cre recombinase; Exhibits; Family suidae; Fibrosis; Fluorescence; Genes; HLA-A gene; Heart Block; Heart Injuries; Homer 1; Human Resources; IRAK1 gene; In Vitro; Infarction; Mediating; Mesenchymal Stem Cells; Methods; MicroRNAs; Modeling; Molecular; Molecular Target; Mus; Myocardial; Myocardial Infarction; Myocardial dysfunction; Myocardium; Neonatal; PTPRC gene; Parents; Production; Proteins; Proto-Oncogene Protein c-kit; Recovery; Recovery of Function; Regulation; Reporter; Rodent; Rodent Model; Role; Serum; Signal Transduction; Source; TRAF6 gene; Techniques; Testing; Therapeutic; Therapeutic Effect; Transgenic Organisms; Treatment Efficacy; base; cardiac regeneration; cardiac repair; cellular targeting; clinical efficacy; combinatorial; design; effective therapy; exosome; heart function; heat-shock factor 1; improved; inhibitor; injured; injury and repair; knock-down; neonatal human; next generation; non-genetic; overexpression; pH gradient; paracrine; pre-clinical; recruit; regenerative; response to injury; restoration; stem cell differentiation; stem cell therapy; stem cells; therapeutic miRNA; tissue regeneration

SUMMARY The potential of stem cell therapies to restore heart function and promote tissue regeneration in response to injury is evident by the completed and recruiting clinical trials. However, the beneficial effects in these clinical trials using adult CPCs ( are modest. We have demonstrated that neonatal CPCs have superior efficacy in repairing the injured heart compared to aCPCs and recently, revealed that the nCPCs beneficial effect is mediated by a paracrine mechanism through a secretome. Exosomes derived from various type of stem cells/progenitor cells have been shown to mediate stem cell-triggered therapeutic effects on the injured heart through their miRNA cargo. Thus, we hypothesize that HSF1 in nCPCs promotes production of exosomes, functional exosomal miRNAs cargo, and exosome acquisition to recipient cells. The presence of therapeutic miRNAs including miR199a, miR590 and miR146a in nCPC exosomes stimulates cardiomyocyte proliferation and suppresses apoptosis and fibrosis by targeting specific genes leading to the restoration of cardiac function in the injured heart. To test our hypothesis, we proposed three specific aims. Aim 1 will elucidate the functional role of HSF1 in exosome biogenesis and exosomal cargo regulation. We will examine whether HSF1 knockdown in nCPCs will abolish their superior ability in generating functional EXO and EXO cargos, and if HSF1 overexpression in aCPCs will achieve comparable capability to that of nCPCs in EXO therapeutic functionality. Aim 2 will identify the major exosome molecular target in exosome-recipient cardiac cells and determine whether HSF1 is essential for exosome acquisition. We will identify cellular targets of exosomes and if HSF1 is essential for the retention of donor EXOs. We will examine whether Homer1, Clic5, TRAF6 and IRAK1 as EXO major molecular targets in cardiac function recovery. Aim 3 will determine whether the therapeutic miRNAs mediate the effect of exosomes and whether further miRNA enrichment achieves optimal cardiac recovery. We will examine the effects of exosomal miRs-199a, 590, 146a on cardiac recovery.

概括 干细胞疗法恢复心脏功能并促进组织再生的潜力 完成和招募临床试验可以明显看出伤害。但是，这些临床的有益影响 使用成人CPC进行的试验（谦虚。我们已经证明了新生儿CPC具有较高的功效 与ACPC相比，修复受伤的心脏，最近发现NCPC有益效果是 由旁分泌机制介导的，通过分泌组机制介导。源自各种类型的茎的外泌体 细胞/祖细胞已显示可介导干细胞触发的对受伤心脏的治疗作用 通过他们的mirna货物。因此，我们假设NCPC中的HSF1促进了外泌体的产生， 功能性外泌体miRNA货物和对受体细胞的外泌体采集。存在 NCPC外泌体中包括miR199a，miR590和miR146a在内的治疗miRNA刺激 心肌细胞增殖并通过针对特定基因领先的特定基因来抑制凋亡和纤维化 为了恢复受伤的心脏中心脏功能。为了检验我们的假设，我们提出了三个特定的特定 目标。 AIM 1将阐明HSF1在外泌体生物发生和外泌体货物中的功能作用 规定。我们将检查NCPC中的HSF1敲低是否会废除其产生的卓越能力 功能性EXO和EXO Cargos，如果ACPC中的HSF1过表达将获得可比的能力 EXO治疗功能中的NCPC。 AIM 2将确定主要的外泌体分子靶 外泌体恢复心脏细胞，并确定HSF1是否对于外部采集至关重要。我们 将确定外泌体的细胞靶标，以及HSF1是否对于保留供体外ex剂至关重要。我们将检查 HOMER1，CLIC5，TRAF6和IRAK1是否是心脏功能恢复中的主要分子靶标。目标3 将确定治疗性miRNA是否介导外泌体的作用以及是否进一步 miRNA富集可实现最佳心脏恢复。我们将检查外泌体miRS-199a的影响， 590，146a关于心脏恢复。