Cell therapy regulates cardiac healing through innate immune response

细胞疗法通过先天免疫反应调节心脏愈合

• 批准号: 10561163
• 负责人: Jeffery D Molkentin
• 金额: $ 3.65万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2023-04-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10561163
• 关键词: Acute; Adopted; Adult; Apoptosis; Area; Atherosclerosis; Bacteria; Basic Science; Bioinformatics; Biology; Blood Vessels; Cardiac; Cardiac Death; Cardiac Myocytes; Cardiovascular system; Cause of Death; Cell Therapy; Cell secretion; Cells; Cicatrix; Clinical Data; Clinical Trials; Compensation; Complement Activation; DNA; Data; Dendritic Cells; Disease; Endothelial Cells; Event; Fibroblasts; Genes; Goals; Heart; Heart Diseases; Heart Injuries; Heart failure; Human; Immune; Immune response; Immune signaling; Immune system; Infarction; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Injection of therapeutic agent; Injections; Injury; Innate Immune Response; Literature; Longevity; Macrophage; Mediating; Mus; Muscle Cells; Myocardial Infarction; Natural regeneration; Nature; Neurosecretory Systems; Outcome; Pathway interactions; Patients; Pattern recognition receptor; Process; Production; Proteins; RNA; Rejuvenation; Reporting; Reproducibility; Research; Resolution; Rodent Model; Signal Pathway; Signal Transduction; Stimulator of Interferon Genes; Sting Injury; Structure; Therapeutic; Therapy trial; Time; Tissue Expansion; Tissues; Toll-like receptors; Uncertainty; Virus; Western World; Work; adult stem cell; cardiac regeneration; cell type; direct application; fungus; genetic manipulation; healing; improved; in vivo; injured; innate immune mechanisms; ischemic injury; mouse genetics; neutrophil; novel; novel therapeutics; paracrine; physical property; protective effect; repaired; response; response to injury; stem cell therapy; stem cells; transdifferentiation

Abstract Myocardial infarction (MI) due to underlying atherosclerosis is the leading disease sequela that precipitates heart failure in the Western world. Our ability to treat these patients and their heart failure has not progressed beyond a mild 20-30% extension in life span realized some 3 decades ago with neuroendocrine-based management. New therapeutic avenues are needed, the most dramatic of which would be directly generating new cardiomyocyte to regenerate the damaged area of heart tissue. Previous attempts to regenerate the heart through new myocyte production have not been successful despite more than 15 years of research using adult progenitor cells. However, studies with cardiac progenitor cells in rodent models did show a functional benefit to the MI-injured heart, and we and others have identified a novel mechanism of benefit whereby cell therapy has a rejuvenating effect through refinement of the immune response. Indeed, we have shown that cell therapy injections can optimize healing, reduce infarct area expansion and augment scar borderzone physical properties (Vagnozzi et al., 2020, Nature). These beneficial effects were mediated through selective macrophage subtype activity in the heart, underscoring the importance of the immune response in infarct healing and compensation. Here we propose the hypothesis that selective innate immune response signaling pathways, and macrophage subtype polarization can be exploited to further heal MI injury and to explain how cell therapy functions in vivo. Our more specific hypothesis is that MI injury or cell therapy has an underlying protective component through cGAS-Sting in both cardiomyocytes and macrophages, and this can be therapeutically exploited to polarize the immune response for better healing. The specific aims are: AIM #1, To use mouse genetics to identify the specific immune cell-types in the heart that mediate cell therapy-based cardiac rejuvenation post-MI injury. AIM #2, To examine the mechanism of innate immune signaling in the heart through cGAS-Sting. AIM #3, To investigate the mechanisms whereby cell therapy rejuvenates the post-MI injured heart. Such studies will be critical for examining how innate immune signaling at the level of macrophages impacts the heart during an inflammatory injury response or due to cell therapy with the goal of modifying this response to benefit healing in patients.

抽象的 潜在动脉粥样硬化引起的心肌梗塞 (MI) 是主要疾病 在西方世界，这种后遗症会导致心力衰竭。我们有能力治疗这些 患者的心力衰竭进展并未超过轻度 20-30% 大约三十年前通过基于神经内分泌的管理实现了寿命。新的 需要治疗途径，其中最引人注目的是直接 产生新的心肌细胞以再生心脏组织受损区域。 之前通过产生新的心肌细胞来再生心脏的尝试并没有成功。 尽管使用成体祖细胞进行了超过 15 年的研究，但仍取得了成功。 然而，在啮齿动物模型中对心脏祖细胞的研究确实表明了功能性 对心肌梗死损伤的心脏有益，我们和其他人已经确定了一种新的机制 细胞疗法通过改善免疫系统具有恢复活力的效果 回复。事实上，我们已经证明细胞疗法注射可以优化愈合， 减少梗塞面积扩大并增强疤痕边界区的物理特性 （Vagnozzi 等人，2020，《自然》）。这些有益的影响是通过 心脏中选择性巨噬细胞亚型活动，强调了 梗塞愈合和代偿中的免疫反应。这里我们提出假设 选择性先天免疫反应信号通路和巨噬细胞亚型 极化可用于进一步治愈心肌梗死损伤并解释细胞疗法如何 在体内发挥作用。我们更具体的假设是心肌梗死损伤或细胞疗法具有 通过 cGAS-Sting 保护心肌细胞和 巨噬细胞，并且可以在治疗上利用它来极化免疫反应 为了更好的治愈。具体目标是： AIM #1，利用小鼠遗传学来识别 心脏中介导基于细胞疗法的心脏的特定免疫细胞类型 心肌梗死损伤后的恢复活力。目标#2，检查先天免疫机制 通过 cGAS-Sting 在心脏中发出信号。目标#3，研究机制 细胞疗法使心肌梗死后受伤的心脏恢复活力。此类研究至关重要 用于研究巨噬细胞水平的先天免疫信号如何影响 心脏在炎症损伤反应期间或由于细胞治疗的目的 改变这种反应有利于患者的康复。