Cardiac resident macrophages in AV node conduction

心脏常驻巨噬细胞参与房室结传导

• 批准号: 10365141
• 负责人: Maarten Hulsmans
• 金额: $ 76.28万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365141
• 关键词: Ablation; Adopted; Apoptosis; Atrioventricular Block; Autopsy; Biological Assay; Biomedical Engineering; CSF3 gene; Cardiac; Cardiac Myocytes; Cause of Death; Cells; Communication; Confocal Microscopy; Connexin 43; Connexins; Coupling; Data; Devices; Diphtheria Toxin; Disease; Dose; Electrocardiogram; Electrophysiology (science); Etiology; Extracellular Matrix; Fibrosis; Genetic; Granulocyte-Macrophage Colony-Stimulating Factor; Heart; Heterogeneity; Human; Image; Immune; Immunology; Implant; Incidence; Infusion procedures; Injections; Interleukin-4; Location; Macrophage Colony-Stimulating Factor; Mediating; Monitor; Mus; Muscle Cells; Myeloid Cells; Optics; Pacemakers; Parabiosis; Patients; Phenotype; Population; Process; Protocols documentation; Publishing; Recovery; Recovery of Function; Research; Role; Sampling; Somatotropin; Source; Spatial Distribution; Stains; Stromal Cells; System; Techniques; Telemetry; Testing; Time; Tissues; Work; atrioventricular node; base; clinically relevant; experimental study; improved; in vivo; macrophage; monocyte; mortality; multiphoton microscopy; novel; optogenetics; progenitor; single-cell RNA sequencing; targeted treatment; translational goal

Atrioventricular (AV) conduction abnormalities are common and potentially lethal if not treated with a pacemaker. We recently discovered that macrophages inhabit the mouse and human AV node, and that depletion of macrophages in the Cd11bDTR mouse leads to complete AV block. In the normal murine AV node, macrophages electrically couple to conducting cells via connexin 43. This electrotonic coupling creates a source-sink relationship between macrophages and conducting cardiomyocytes. Genetic interference with macrophage-myocyte coupling weakened AV conduction while optogenetically enhanced communication improved AV node function. These data, which we recently published in Cell, establish that resident macrophages augment the fidelity of AV node conduction. We have continued this work by performing survival studies after macrophage depletion, finding that all mice with AV block die. In preliminary work for this application, we adopted an implantable pacemaker system for mice, and were able to pace mice for several weeks. We here propose to use this technique in Cd11bDTR mice. We will conduct studies to better understand the function of AV node macrophages in order to advance our long-term translational goal to one day develop macrophage-targeted therapeutics as a new option for conduction disorders. We will implant pacemakers into Cd11bDTR mice and pace them for up to three months after macrophage depletion. We will test the hypothesis that, if the mice are supported with a pacemaker, spontaneous recovery of AV node conduction will occur due to recovery of tissue macrophages. We will test for AV node recovery by ECG telemetry in conjunction with in vivo electrophysiological and ex vivo optical mapping studies to provide a comprehensive assessment of AV node function. After recovery, we will isolate AV nodes to investigate the cellular and structural landscape with special focus on macrophage numbers, subset heterogeneity and spatial distribution by FACS, single-cell RNA-sequencing and imaging. Using parabiosis, we will determine whether cardiac macrophages repopulate from circulating monocytes or from tissue progenitors. We will further test whether enhancing tissue macrophage numbers will influence AV node recovery. Since AV node macrophages are reduced in mice lacking macrophage colony stimulating factor (M-CSF), we will treat macrophage-depleted mice with M-CSF to test the hypothesis that such treatment will increase local proliferation of remaining AV node macrophages, and thus ushers in recovery of AV node conduction. We will also explore other growth hormones with influence on myeloid cell replenishment. In a translational aim, we will study macrophages, other non-cardiomyocytes and structural remodeling processes in human AV nodes obtained from patients with AV block. Our collaborative application unites an interdisciplinary team with expertise in electrophysiology, immunology and bioengineering. While the novel research plan is ambitious, we believe that our preliminary data demonstrate feasibility and provide us with a unique opportunity to study a question with high clinical relevance.

房室（AV）传导异常是常见的，如果不治疗可能致命