Innate immune response signaling in cardiac injury healing

摘要 由于动脉粥样硬化引起的心肌梗死（MI）是主要疾病 在西方世界导致心力衰竭的后遗症。我们治疗这些 患者和他们的心力衰竭没有进展超过轻度20-30%的扩展， 大约30年前通过基于神经内分泌的管理实现了寿命[1]。 需要新的治疗途径，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的受损区域。 以前通过产生新的心肌细胞来再生心脏的尝试没有成功。 尽管使用成人祖细胞进行了超过18年的研究，但仍然取得了成功。 然而，在啮齿动物模型中对心脏祖细胞的研究确实显示了功能性的 这对MI受伤的心脏有益，尽管我们现在知道这不是由于 显著的新肌细胞产生。相反，我们和其他人发现了一种新的 有益的机制，从而注射的祖细胞具有返老还童的效果， MI-通过完善的免疫反应受损的心脏。我确已证明， 细胞治疗注射可以在最近因缺血而受伤的心脏区域进行， 再灌注（7天后）可以优化愈合，减少梗死面积扩大， 增加疤痕边界区的物理性质（Vageli等人，2020，Nature）。这些 有益的效果是通过选择性巨噬细胞亚型活性介导的， 心脏，强调免疫反应在心血管健康中的重要性， 梗死愈合和代偿。在这里，我们提出的假设，选择性先天 免疫应答信号传导途径和巨噬细胞亚型极化可以是 用来治愈心脏我们更具体的假设是， 通过Toll样受体（TLR）信号传导， 心肌细胞和巨噬细胞，这可以在治疗上利用， 免疫反应来更好地愈合。具体目标是：目标#1，检查 通过TLR信号传导的心脏先天免疫信号传导机制。目标#2，至 诱导改变心脏中的巨噬细胞亚型， 反应和愈合动力学的细胞疗法。目的#3，确定成纤维细胞如何 与心肌梗死后受损心脏中的巨噬细胞亚型沟通以影响愈合 细胞疗法的动力学。这些研究对于研究先天免疫是如何 在巨噬细胞和心肌细胞水平的信号传导在一个过程中影响心脏。 炎症损伤反应，目的是改变这种反应， 治愈病人。

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 [1]. 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 18 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, although we now understand that this is not due to significant new myocyte production. Instead we and others have identified a novel mechanism of benefit whereby injected progenitor cells have a rejuvenating effect on the MI-injured heart through refinement of the immune response. Indeed, we have shown that cell therapy injections that flank the recently injured area of the heart from ischemia- reperfusion (7 days later) 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 cardiovascular health and infarct healing and compensation. Here we propose the hypothesis that selective innate immune response signaling pathways, and macrophage subtype polarization can be exploited to help heal the heart. Our more specific hypothesis is that therapy has an underlying protective component through Toll-like receptor (TLR) signaling 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 examine the mechanism of innate immune signaling in the heart through TLR signaling. AIM #2, To inducibly alter macrophage subtypes in the heart to reprogram the innate immune response and healing dynamics by cell therapy. AIM #3, To determine how fibroblasts communicate with macrophage subtypes in the post-MI injured heart to affect healing dynamics by cell therapy. Such studies will be critical for examining how innate immune signaling at the level of macrophages and cardiomyocytes impacts the heart during an inflammatory injury response with the goal of modifying this response to benefit cardiac healing in patients.