Engineered Atrium: New Autologous Cells for Heart Repair

工程心房：用于心脏修复的新型自体细胞

基本信息

批准号：
7904854
负责人：
MARGARET D ALLEN
金额：
$ 63.44万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7904854
关键词：
3-Dimensional Adult Apoptosis Autologous Biomechanics Biomedical Engineering Blood Blood Clot Blood Vessels Blood capillaries Blood coagulation Cardiac Cardiac Myocytes Cause of Death Cell Survival Cells Clinical Coagulation Process Collagen Complement Complex Connexins Contractile Proteins Contracts Drug Delivery Systems Embryo Endothelium Engineering Fiber Fibroblast Growth Factor 2 Fibrosis Fostering Future Gene Delivery Goals Heart Heart Atrium Heart Diseases Heart failure Human Hydrogels Implant In Vitro Infarction Intravenous Investigation Ischemia Mechanics Mediator of activation protein Methods Modeling Mus Muscle Muscle Cells Myocardial Infarction Myocardium Operative Surgical Procedures Organ Patients Protein Isoforms Public Health Pump Recovery Research Personnel Source Structure Surgeon Surgical Flaps Testing Therapeutic Tight Junctions Time Tissue Engineering Tissue Grafts Tissues Transcription Coactivator Transplantation Troponin T United States Up-Regulation Vascularization Ventricular Ventricular Function Work auricular appendage biglycan blood pump capillary cell type clinical application clinically relevant cobaltiprotoporphyrin conditioning design embryonic stem cell gene therapy heart cell heme oxygenase-1 human tissue implantation improved in vivo inhibitor/antagonist injured interstitial meetings multidisciplinary muscle form new technology novel novel strategies patient population preconditioning prevent programs repaired research study scaffold

项目摘要

DESCRIPTION (provided by applicant): Autologous atrial appendage tissue has not been pursued as a cell source for ventricular myocardial infarct repair although it is the only expendable portion of the human heart. To date, the use of adult cardiomyocytes in tissue engineering has been limited by their rapid apoptosis in vitro and in vivo. In preliminary work, however, it was demonstrated that ex vivo induction of heme oxygenase-1 (HO-1), a mediator of late pre- conditioning, could increase adult cardiomyocyte survival by 140% at 14 days following in vivo implantation. Furthermore, almost 50% of treated patches began spontaneous, synchronized contraction by 14 days, unlike patches implanted directly without culture, patches cultured without HO-1 induction, or patches cultured with specific HO-1 inhibitors. Implanted as three-dimensional flattened patches, myocytes in patches with HO-1 upregulation spontaneously remodeled around vascular spaces to form pumping chambers filled with non- clotting blood. These findings suggest that adult cardiomyocytes may have more plasticity than previously thought, and that, with optimization, might be suitable as an autologous cell source for infarct repair and cardiac tissue engineering. Experiments will investigate clinically relevant novel strategies designed to meet four current challenges to the use of autologous adult cardiomyocytes: improving myocyte tolerance to ischemia; integrating patches with host vasculature; reducing fibrosis; and maximizing function after implantation on the heart. To overcome myocyte apoptosis, transcriptional activators of HO-1 will be delivered both ex vivo and intravenously, testing a new permeabilizing agent as a means to improve drug delivery to the central cells of three-dimensional tissue grafts. Hydrogels with timed release of bFGF will be applied with mobilized omental pedicles to foster integration with host vasculature and create a high volume extracardiac blood source to support the patch. Local AAV gene delivery of HO-1 to the patch will be used to explore the long-term matrix modulatory effects of HO-1 on interstitial fibrosis. Finally, the consequences of patch myofiber alignment and ischemic re-programming of contractile proteins on patch biomechanics and ventricular function will be assessed. A unique aspect of the project is the opportunity to use human atrial tissue from cardiac surgical patients to replace mouse tissue as a donor source in parallel experiments. Thus, experimental strategies will be tested in tissue from the very patient population likely to benefit from this new technology in the future. This project is a multidisciplinary effort between surgeons, bioengineers, and matrix biologists, working together toward an important therapeutic endpoint with expected early clinical applicability. Relevance to public health: Heart disease is the leading cause of death in the United States. After a heart attack, heart muscle mass is irreversibly lost, often leading to heart failure. Current methods under investigation to replace lost muscle propose using embryonic stem cells or cell types that have not been shown to transform into heart muscle. This project investigates the novel, but likely possibility that the patient's own expendable heart muscle cells from the atrial chamber could be modified to allow them to survive transplantation onto the injured ventricle to prevent and treat heart failure.

描述（由申请人提供）：自体心房附属组织尚未被追捕作为心室心肌梗死修复的细胞来源，尽管它是人心脏中唯一的可消耗性部分。迄今为止，在组织工程中使用成年心肌细胞已受其体外和体内快速凋亡的限制。然而，在初步工作中，证明血红素氧酶-1（HO-1）的体内诱导是后期预处理的介体，可以在体内植入后14天将成人心肌细胞存活率提高140％。此外，几乎50％的处理斑块开始自发，在14天后开始同步收缩，这与没有培养的没有培养的斑块不同，没有HO-1诱导的斑块或用特定的HO-1抑制剂培养的斑块。植入三维扁平的斑块，在斑块中植入，HO-1上调自发地周围的HO-1上调，以形成充满非凝结血液的抽水室。这些发现表明，成年心肌细胞的可塑性可能比以前想象的要多，并且通过优化，可能是梗死修复和心脏组织工程的自体细胞来源。实验将研究旨在应对使用自体成年心肌细胞的四个挑战的临床相关新型策略：提高肌细胞对缺血的耐受性；将补丁与宿主脉管系统整合；减少纤维化；并在植入心脏后最大化功能。为了克服心肌细胞凋亡，HO-1的转录激活剂将在体内和静脉内递送，测试一种新的透化剂，作为改善药物递送到三维组织移植物中心细胞的手段。与定时释放BFGF的水凝胶将与动员的胶质椎弓根一起使用，以与宿主脉管系统促进整合，并创建大容量的外部血液源以支持该斑块。 HO-1向斑块的局部AAV基因递送将用于探索HO-1对间质纤维化的长期基质调节作用。最后，将评估收缩蛋白对斑块生物力学和心室功能的斑块肌动物比对的后果。该项目的一个独特方面是有机会在平行实验中使用心脏外科患者的人心房组织将小鼠组织作为供体来源。因此，将来可能会在将来从这项新技术中受益的非常患者人群的组织中测试实验策略。该项目是外科医生，生物工程师和基质生物学家之间的多学科工作，共同朝着重要的治疗终点，具有预期的早期临床适用性。与公共卫生有关：心脏病是美国死亡的主要原因。心脏病发作后，心肌质量会不可逆转地丢失，通常会导致心力衰竭。目前正在研究的方法替代肌肉丧失的方法提出了使用尚未证明转化为心脏肌肉的胚胎干细胞或细胞类型的方法。该项目调查了该小说，但可能会修改患者自身的可消耗性心肌细胞，以使它们能够在受伤的心室上移植以预防和治疗心力衰竭。