Cell therapy regulates cardiac healing through innate immune response

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 得益于细胞疗法通过改善免疫系统而起到恢复活力的作用 回应。事实上，我们已经证明，细胞疗法注射可以优化愈合， 减少梗死面积扩大，增强疤痕交界区物理特性 (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 极化可以用来进一步治疗心肌梗死损伤，并解释细胞疗法是如何 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有 心肌细胞中cGAS-Sting的潜在保护成分 巨噬细胞，这可以在治疗上用来极化免疫反应 为了更好的康复。具体目标是：目标1，利用小鼠遗传学来鉴定 心脏中介导基于细胞治疗的心脏的特定免疫细胞类型 心肌梗死损伤后恢复活力。目的#2，研究先天免疫的机制 通过cGAS-Sting在心脏中传递信号。目的#3，探讨其作用机制 细胞疗法使心肌梗死后受损的心脏恢复活力。这样的研究将是至关重要的 为了研究巨噬细胞水平上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而达到的目标 改变这种反应，以利于患者的康复。

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.