Project 3 - Cell Therapy and Remodeling

项目3——细胞治疗与重塑

• 批准号: 9980485
• 负责人: Steven P Jones
• 金额: $ 32.37万
• 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/9980485
• 关键词: Acute; Address; Affect; Animals; Attenuated; Autologous; Binding; CD44 Antigens; CD44 gene; Cardiac; Cell Shape; Cell Therapy; Cell Transplantation; 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; acute wound; clinical translation; effective intervention; gain of function; improved; in vivo Model; innovation; insight; interest; ischemic injury; lens; novel; paracrine; pre-clinical; preclinical study; programs; receptor; repaired; response; response to injury; stem; synergism; transdifferentiation; wound healing

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如何发挥作用的机制见解，但临床前研究通常 报告纤维化减少。因此，要了解细胞疗法如何限制重塑，我们必须首先了解 修复细胞如何与基质室相互作用。在正常心脏中，成纤维细胞对于 维持细胞外基质。梗塞后，成纤维细胞在急性伤口中发挥积极作用 康复。尽管这种表型激活对于急性缺血性损伤反应是必要的， 成纤维细胞长期活化，导致缺血后病理。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，并将识别 CMC- 介导成纤维细胞活化的变化。因为心梗后心脏的特点是平衡发生变化 透明质酸 (HA) 代谢过程中产生的 HA 多于降解的 HA，HA 积累可能 有助于持续的成纤维细胞激活并支持未解决的炎症。此外，我们推断 细胞疗法通过恢复失调的 HA 代谢的平衡来影响心肌修复，这在很大程度上是 由活化的成纤维细胞繁殖。我们将进行概念验证研究，以证明 HA 是否以及如何 修复细胞中的代谢酶可以调节其在缺血后体内模型中的能力 心肌修复。我们将确定赋予修复能力的特定受体-配体相互作用 治疗细胞。尽管上述目标本身就值得追求，但我们认为它们应该 通过平移镜头进一步检查，因为修复细胞的临床前研究使用健康细胞 作为细胞供体的动物；然而，自体细胞的临床试验使用心力衰竭 (HF) 患者作为 捐助者和受赠者。这种临床前/临床二分法造成了相当大的转化障碍。因为 梗塞后基质室发生显着变化，从中衍生出修复细胞 可能与幼稚的修复细胞不同。事实上，我们的初步数据表明心力衰竭衍生的 CMC lack reparative competence, which may stem from their inability to properly metabolize post-MI stromal 成分，例如HA。我们将识别并纠正因心力衰竭而导致的无能 CMC 的缺陷。 因此，我们的中心假设认为，修复细胞通过识别来减弱心室重塑 以及对特定基质成分的反应，这些成分在心脏衰竭的 CMC 中丢失。我们将测试 这一假设通过以下协同目标实现：1) 阐明 CMC 对成纤维细胞活化的影响； 2） 确定 CMC 如何与受体心脏相互作用，以限制适应不良的重塑； 3）识别与救援 心力衰竭衍生的修复细胞的缺陷机制​​。因此，我们将首次展示 CMC 如何 塑造 MI 后基质以限制成纤维细胞活化。我们还将确定修复的原因 心力衰竭衍生的 CMC 的无能，并通过挽救其能力来恢复其能力 代谢HA。项目 3 的集体见解将从根本上改变未来的细胞治疗研究。