The Role of Cardiomyogenic Lineage Commitment in Cardiac Mesenchymal Cell-Mediated Extracellular Vesicle Signaling and Cardiac Repair

心肌源性谱系定型在心脏间充质细胞介导的细胞外囊泡信号传导和心脏修复中的作用

• 批准号: 10094072
• 负责人: Joseph B Moore IV
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094072
• 关键词: Affect; Azacitidine; Biological; Bone Marrow; Cardiac; Cardiovascular system; Cell Lineage; Cell Survival; Cell Therapy; Cell Transplantation; Cells; Characteristics; Chronic; Clinical Trials; Competence; Congestive Heart Failure; Dependence; Development; Exhibits; Future; GATA4 gene; Genetic; Goals; Heart; Heart failure; Human; In Vitro; Infarction; Injections; Injury; Left Ventricular Function; Light; Link; Mediating; Mediator of activation protein; Mesenchymal; Methods; Modality; Modeling; Modification; Muscle Cells; Myocardial Infarction; Nude Rats; Paracrine Communication; Pathway interactions; Patients; Pharmacology; Population; Production; Rattus; Research; Role; Signal Transduction; Structure; Testing; Therapeutic; Tissues; Treatment Efficacy; Variant; Ventricular; Ventricular Remodeling; Work; arteriole; cardiac regeneration; cardiac repair; cell type; cytokine; early phase clinical trial; extracellular vesicles; heart function; improved; neovascularization; novel; pre-clinical; release factor; repaired; reparative capacity; retention rate; stem cells; transcription factor

Clinical trials for cell therapy reveal only modest benefits on cardiac function in heart failure (HF) patients – leaving the future of this therapeutic modality uncertain. Despite years of research on the topic, the cell therapy field remains engrossed in controversies regarding the mechanism(s) of action of donor cells and the cell type best suited to promote cardiac repair. Two competing hypotheses have been forwarded to explain the mechanisms underlying cell therapy-mediated cardiac repair, namely donor cell direct differentiation (contributing to new cardiac parenchyma) and paracrine signaling (promotion of endogenous repair mechanisms through cytokine and/or extracellular vesicle (EV) secretion). Given that donor cell populations exhibit poor rates of retention and limited long-term persistence after delivery in HF models, paracrine signaling is viewed as a major mechanism of cell-mediated cardiac repair. However, there is also evidence implicating a link between therapeutic efficacy and donor cell cardiovascular fate decisions; although the mechanisms remain unknown. It is known that different cell types possess distinct trophic factor secretion profiles and paracrine signaling activities. Thus, we posit that cardiovascular cell lineage commitment-dependent variations in paracrine signaling are likely to have a significant impact on donor cell reparative capacity in cell-mediated cardiac repair. Further, as EVs have been identified as important mediators of progenitor cell-induced cardiac regeneration, we hypothesize that donor cell cardiomyogenic lineage commitment regulates the expression and synthesis of EV-resident cardiotrophic factors, which mediate cardiac repair. To test this hypothesis, we will use genetic and pharmacologic approaches for enhancing cardiogenic factor expression to assess the effects of cardiomyogenic lineage commitment on the reparative capacity of cardiac mesenchymal cells (CMCs) and lineage-dependent adaptations in CMC EV signaling. Aim 1 will interrogate the impact of genetic- and pharmacologic-mediated induction of cardiogenic factor expression on CMC cardiovascular lineage commitment and EV paracrine signaling. Aim 2 will assess the effect of cardiomyogenic lineage commitment on the reparative capacity of CMCs following administration in a chronic infarct model. Aim 3 will evaluate the consequences of EV administration, derived from naïve and cardiomyogenic lineage-committed CMCs, on cardiac repair. The results of this project will establish an unidentified link between progenitor cell cardiovascular lineage commitment and modifications in EV secretion/paracrine signaling, as well as elucidate novel targets and pathways that may be exploited to enhance the efficacy of cell therapy.

细胞疗法的临床试验显示，对心力衰竭（HF）患者的心脏功能只有适度的益处- 使得这种治疗方式的未来不确定。尽管对这个话题进行了多年的研究， 治疗领域仍然全神贯注于关于供体细胞的作用机制和 最适合促进心脏修复的细胞类型。两个相互竞争的假设已经提出来解释， 细胞治疗介导的心脏修复机制，即供体细胞直接分化 （促进新的心脏实质）和旁分泌信号（促进内源性修复） 通过细胞因子和/或细胞外囊泡（EV）分泌的机制）。鉴于供体细胞数量 在HF模型中表现出较差的保留率和有限的长期持续性，旁分泌信号传导 被认为是细胞介导的心脏修复的主要机制。然而，也有证据表明， 治疗效果和供体细胞心血管命运决定之间的联系;尽管机制 仍然未知。已知不同的细胞类型具有不同的营养因子分泌谱， 旁分泌信号活动。因此，我们认为，心血管细胞系的承诺依赖性变化， 在旁分泌信号可能有显着影响供体细胞修复能力的细胞介导的 心脏修复此外，由于EV已被鉴定为祖细胞诱导的心脏炎症的重要介质， 再生，我们假设供体细胞心肌样谱系承诺调节表达 以及介导心脏修复的EV驻留心肌营养因子的合成。为了验证这个假设，我们 将使用遗传和药理学方法来增强心源性因子的表达， 心肌源性谱系定型对心肌间充质细胞修复能力的影响 （CMC）和CMC EV信号传导中的谱系依赖性适应。目标1将询问遗传的影响- 和药理学介导的CMC心血管谱系上心源性因子表达的诱导 承诺和EV旁分泌信号。目的2将评估心肌源性谱系定型的作用 对慢性梗塞模型中施用后CMC的修复能力的影响。目标3将评估 EV给药的后果，来自幼稚和心肌源性谱系定向CMC， 心脏修复这个项目的结果将建立一个未确定的联系祖细胞 心血管谱系承诺和EV分泌/旁分泌信号传导的修饰，以及阐明 新的目标和途径，可以利用，以提高细胞治疗的功效。