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.

总结 干细胞疗法在恢复心脏功能和促进组织再生方面的潜力 已完成的和招募的临床试验证明了损伤。然而，这些临床上的有益效果 使用成人CPC的试验是适度的。我们已经证明新生儿CPC在以下方面具有上级功效： 与aCPCs相比，nCPCs修复受损的心脏，最近，揭示了nCPCs的有益作用是 通过分泌体由旁分泌机制介导。来源于各种类型茎的外来体 细胞/祖细胞已经显示出介导干细胞触发的对受损心脏的治疗作用 通过他们的miRNA货物。因此，我们假设nCPC中的HSF 1促进了外泌体的产生， 功能性外泌体miRNA货物，以及外泌体向受体细胞的获取。的存在 nCPC外泌体中包括miR 199 a、miR 590和miR 146 a的治疗性miRNAs刺激 心肌细胞增殖和抑制细胞凋亡和纤维化，通过靶向特定基因， 恢复受损心脏的心脏功能为了验证我们的假设，我们提出了三个具体的 目标。目的1将阐明HSF 1在外泌体生物发生和外泌体货物中的功能作用 调控我们将研究nCPC中的HSF 1敲低是否会消除它们在产生HSF 1方面的上级能力。 功能性EXO和EXO货物，并且如果aCPC中的HSF 1过表达将实现与 nCPC在EXO治疗功能中的作用。目的2将确定主要的外泌体分子靶点， 外泌体受体心脏细胞，并确定是否HSF 1是外泌体收购所必需的。我们 将确定外来体的细胞靶点，以及HSF 1是否对保留供体EXO至关重要。我们将研究 Homer 1、Clic 5、TRAF 6和IRAK 1是否为EXO心功能恢复的主要分子靶点。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富集实现最佳心脏恢复。我们将研究外泌体miR-199 a的作用， 590，146 a心脏复苏。