Innate Immune Response in Cardiac Healing and Rejuvenation

摘要 由潜在的动脉粥样硬化引起的心肌梗死(MI)是主要疾病 在西方世界引发心力衰竭的后遗症。我们治疗这些疾病的能力 患者和他们的心力衰竭进展没有超过20%-30%的轻微延长 寿命在大约30年前通过基于神经内分泌的管理实现。新的 需要治疗途径，其中最戏剧性的途径将是直接 产生新的心肌细胞以再生受损的心脏组织区域。 以前通过产生新的心肌细胞来再生心脏的尝试没有 尽管使用成体祖细胞进行了15年多的研究，但仍取得了成功。 然而，在啮齿动物模型中对心脏前体细胞的研究确实显示了一种功能 对心肌梗死损伤的心脏有好处，我们和其他人已经确定了一种新的机制 好处，即注射的祖细胞通过精炼 免疫反应。事实上，我们已经证明，细胞疗法注射可以优化 愈合，减少梗死区扩大，增强疤痕交界区的物理特性 (Vagnozzi等人，2020年，《自然》)。这些有益的影响是通过 心脏中的选择性巨噬细胞亚型活动，强调了 脑梗塞愈合和代偿过程中的免疫反应。在这里，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 极化可以被用来进一步治疗心肌梗死损伤。我们更具体的假设是 心肌梗死损伤或细胞疗法通过cGAS具有潜在的保护成分- 在心肌细胞和巨噬细胞中都有刺痛，这可以用于治疗 被用来极化免疫反应，以获得更好的愈合。具体目标是： 目的#1，利用小鼠遗传学鉴定心脏中的特定免疫细胞类型 它介导了基于细胞疗法的心肌梗死后心脏复壮。目标2，检查 心脏天然免疫信号通过cGAS-Sting的机制。目标#3，以 探讨细胞疗法使心肌梗死后受损心脏恢复活力的机制。 这类研究对于检验先天免疫信号如何在 巨噬细胞在炎症损伤反应中或由于细胞而影响心脏 治疗的目的是改变这种反应，以利于患者的愈合。

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 injected progenitor cells had 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. 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.