Project 3 - Cell Therapy and Remodeling

项目3——细胞治疗与重塑

• 批准号: 9551408
• 负责人: Steven P Jones
• 金额: $ 32.23万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9551408
• 关键词: Acute; Address; Affect; Animals; Attenuated; Autologous; Binding; CD44 Antigens; CD44 gene; Cardiac; Cell Shape; Cell Therapy; Cell Transplants; Cells; Chronic; Clinical; Clinical Trials; Collaborations; Competence; Data; Defect; Environment; Enzymes; Equilibrium; Event; Extracellular Matrix; Extravasation; Family suidae; Fibroblasts; Fibrosis; Future; Goals; Heart; Heart failure; Hyaluronan; Hyaluronidase; Infarction; Inflammation; Inflammatory; Injections; Leukocytes; Ligands; Logic; Mediating; Mesenchymal; Metabolism; Modeling; Mus; Muscle; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myofibroblast; Pathology; Patients; Phenotype; Positioning Attribute; Process; Production; Recording of previous events; Reporting; Response Elements; Role; Severities; Signal Transduction; Source; Stromal Cells; Testing; Therapeutic; Time; Ventricular Function; Ventricular Remodeling; Work; Wound Healing; clinical translation; effective intervention; gain of function; improved; in vivo Model; innovation; insight; interest; lens; novel; paracrine; pre-clinical; preclinical study; programs; receptor; repaired; response; response to injury; stem; synergism; transdifferentiation

Despite the dearth of mechanistic insights into precisely how cell therapy works, preclinical studies commonly report a reduction in fibrosis. Thus, to understand how cell therapy limits remodeling, we must first appreciate how reparative cells interact with the stromal compartment. In the normal heart, fibroblasts are essential in maintaining the extracellular matrix. Following infarction, fibroblasts assume an active role in acute wound healing. Although this phenotypic activation is necessary for the acute post-ischemic injury response, fibroblasts become chronically activated, which contributes to post-ischemic pathology. Project 3 will elucidate whether and how cardiac mesenchymal cells (CMCs) interact with the recipient heart and will identify CMC- mediated changes in fibroblast activation. Because the post-MI heart is characterized by a shift in the balance of hyaluronan (HA) metabolism in which more HA is produced than is degraded, HA accumulation may contribute to persistent fibroblast activation and support unresolved inflammation. Furthermore, we reason that cell therapy effects myocardial repair by restoring balance to dysregulated HA metabolism, which is largely propagated by activated fibroblasts. We will perform proof-of-concept studies to show whether and how HA metabolizing enzymes in reparative cells may regulate their competence in in vivo models of post-ischemic myocardial repair. We will identify specific receptor-ligand interactions that confer reparative competence to therapeutic cells. Although the aforementioned goals are worthy of pursuit on their own, we argue they should be examined further through a translational lens because preclinical studies of reparative cells use healthy animals as cell donors; however, clinical trials of autologous cells use heart failure (HF) patients as both donors and recipients. This preclinical/clinical dichotomy creates a sizeable translational barrier. Because significant changes occur in the stromal compartment following infarction, reparative cells derived therefrom likely differ from naïve reparative cells. Indeed, our preliminary data indicate that heart failure-derived CMCs lack reparative competence, which may stem from their inability to properly metabolize post-MI stromal components, such as HA. We will identify and correct defects in incompetent, heart failure-derived CMCs. Thus, our central hypothesis holds that reparative cells attenuate ventricular remodeling through recognition of and response to specific stromal components, which are lost in CMCs derived from failing hearts. We will test this hypothesis through these synergistic aims: 1) Elucidate the impact of CMCs on fibroblast activation; 2) Determine how CMCs interact with the recipient heart to limit maladaptive remodeling; 3) Identify and rescue defective mechanisms in heart failure-derived reparative cells. Thus, we will show, for the first time, how CMCs shape the post-MI stroma to limit fibroblast activation. We will also identify reasons for reparative incompetence in heart failure-derived CMCs and restore their competence by rescuing their capacity to metabolize HA. Collective insights from Project 3 will fundamentally change future cell therapy studies.

尽管缺乏对细胞疗法确切工作原理的机械论见解，但临床前研究通常 报告纤维化减少。因此，要了解细胞疗法是如何限制重塑的，我们必须首先了解 修复细胞如何与间质隔室相互作用。在正常心脏中，成纤维细胞在 维持细胞外基质。脑梗塞后，成纤维细胞在急性创面中发挥积极作用 治愈。尽管这种表型激活对于急性缺血后损伤反应是必要的， 成纤维细胞被慢性激活，这有助于缺血后的病理。项目3将阐明 心脏间充质细胞(CMC)是否以及如何与受体心脏相互作用，并识别CMC- 介导成纤维细胞活化的变化。因为心肌梗死后心脏的特征是平衡的改变 在透明质酸(HA)代谢中，产生的HA多于被降解的HA，HA的积累可能 有助于持久的成纤维细胞激活，并支持未消退的炎症。此外，我们认为 细胞治疗通过恢复失衡的HA代谢的平衡来影响心肌修复，这在很大程度上是 由激活的成纤维细胞繁殖。我们会进行概念验证研究，以显示医管局是否及如何 修复细胞中的代谢酶可能调节其在体内缺血后模型中的活性 心肌修复。我们将确定特定的受体-配体相互作用，赋予修复能力 治疗性细胞。尽管上述目标本身值得追求，但我们认为它们应该 通过平移透镜进一步检查，因为修复细胞的临床前研究使用的是健康的 动物作为细胞供体；然而，自体细胞的临床试验使用心力衰竭(HF)患者作为两者 捐赠者和接受者。这种临床前/临床二分法造成了相当大的翻译障碍。因为 脑梗塞后间质间隔发生显著变化，由此衍生的修复性细胞 很可能不同于幼稚的修复性细胞。事实上，我们的初步数据表明，心力衰竭衍生的巨噬细胞 缺乏修复能力，这可能源于他们无法正确代谢心肌梗死后的间质 组件，如HA。我们将识别和纠正不能、心力衰竭来源的CMCs中的缺陷。 因此，我们的中心假设认为，修复细胞通过识别 以及对特定的基质成分的反应，这些成分在衰竭的心脏来源的CMCs中丢失。我们将测试 这一假说通过这些协同作用的目的：1)阐明CMCs对成纤维细胞激活的影响； 确定CMCs如何与受体心脏相互作用以限制不良适应重塑；3)识别和抢救 心力衰竭来源的修复细胞中的缺陷机制。因此，我们将第一次展示CMCS是如何 塑造心肌梗死后间质以限制成纤维细胞的激活。我们还将确定赔偿的原因 心衰所致的CMC的功能不全通过挽救它们的能力来恢复它们的能力 代谢透明质酸。来自项目3的集体见解将从根本上改变未来的细胞治疗研究。