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Cardiovascular Impact of Gata4 Loss in the c-Kit Lineage

c-Kit 谱系中 Gata4 缺失对心血管的影响

基本信息

批准号：
9768527
负责人：
Bryan D Maliken
金额：
$ 3.78万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2020-05-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9768527
关键词：
Address Adult Apoptosis Appearance Area Autologous Blood Vessels Bone Marrow Bone Marrow Transplantation Cardiac Cardiac Myocytes Cardiovascular system Cause of Death Cell Lineage Cell Therapy Cell Transplantation Cell Transplants Cells Cicatrix Clinical Clinical Trials Coronary Coronary artery Development Echocardiography Endothelial Cells Endothelium Enterobacteria phage P1 Cre recombinase Epidemic Evaluation Event Flow Cytometry GATA4 gene Gene Expression Generations Genetic Goals Heart Heart Injuries Homeostasis Human Immunofluorescence Immunologic In Vitro Incentives Individual Infarction Infiltration Infusion procedures Injury Investigation Ischemia Knock-in Mouse Knock-out Link Mediating Modeling Monitor Mus Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Natural regeneration Physiological Population Prevention Proto-Oncogene Protein c-kit Public Health Publishing Receptor Protein-Tyrosine Kinases Recovery Reperfusion Injury Reperfusion Therapy Reporting Research Personnel Role Site Source Stem cells Supporting Cell Therapeutic Time Transcriptional Regulation Tube Vascular Endothelium Vascular Permeabilities Vascularization Vision Work angiogenesis artery infusion bone cardiac regeneration cardiac repair experimental study functional improvement global health heart dimension/size heart function improved in vivo insight migration neovascularization new therapeutic target novel prophylactic regenerative repaired stem transcription factor

项目摘要

Project Summary Ischemic heart disease is the leading cause of death worldwide. To approach this major public health epidemic, two prevailing areas of study have emerged: 1) Cell therapy aimed at delivering culture-expanded pluripotent cells by coronary artery infusion after an ischemic event, and 2) Endogenous cardiac progenitor cells (CPCs) and their potential role for in vivo renewal and regeneration of the myocardium. Initially these two topics seemed inextricably linked, but it is now becoming clear that while delivery of CPCs for therapy may provide some mechanistically-unexplained benefit, the retention of these cells into the myocardium is marginal and de novo cardiomyocyte differentiation is even less common. A population of putative CPCs, marked by the tyrosine kinase receptor, c-Kit, have been a common focus in both areas of study. Our lab recently published a genetic lineage tracing model demonstrating the cardiac contribution of the Kit lineage in the heart which showed conclusively that Kit-derived cells rarely become cardiomyocytes, but have a high propensity for the formation of vascular endothelium. Furthermore, this study demonstrated that approximately 80% of Kit lineage-traced cardiomyocytes were actually derived from fusion events and the sought-after de novo cardiomyocyte was even more rare than originally believed. To validate this study, we aimed to eliminate the ability of Kit-derived cells to make any de novo cardiomyocytes by knocking out essential cardiomyogenic transcription factor, Gata4, theoretically allowing only for lineage-traced cardiomyocytes derived from fusion. Interestingly, the appearance of Kit lineage-traced cardiomyocytes due to fusion increased dramatically with the loss of Gata4 in the Kit lineage, and, furthermore, we observed a dramatic increase of both Kit-lineage cells in the heart and total cardiac vascular endothelium. We now hypothesize that what is uniting these findings is a novel role for Gata4 in the adult vascular endothelium, and what initially appeared to be an interesting driver of innate fusigenic character with cardiomyocytes is most likely an incidental readout due to increased vascular permeability and neoangiogenesis. While many GATA transcription factors have had previously reported roles in vascular development, including Gata4, few studies have focused on adult vascular homeostasis. Better understanding of this Gata4-mediated transcriptional control of vascular expansion could provide meaningful insight into mechanisms of cardiac renewal and repair. To address this novel role of Gata4 in the cardiac vascular endothelium, we will pursue the following aims: (1) Determine whether endothelial-specific loss of Gata4 leads to increased vascular permeability and enhanced angiogenesis; (2) Assess changes in cardiac recovery after deletion of Gata4 in the adult cardiac endothelium.

项目总结