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.

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