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）：尽管自体心耳组织是人类心脏的唯一消耗部分，但尚未将其作为心室心肌梗塞修复的细胞来源。迄今为止，成体心肌细胞在组织工程中的应用因其在体外和体内的快速凋亡而受到限制。然而，初步工作表明，血红素加氧酶-1 (HO-1)（一种后期预处理的介质）的离体诱导可以在体内植入后 14 天将成体心肌细胞的存活率提高 140%。此外，与未经培养直接植入的贴片、未经 HO-1 诱导培养的贴片或使用特定 HO-1 抑制剂培养的贴片不同，几乎 50% 的处理贴片在 14 天时开始自发、同步收缩。作为三维扁平斑块植入后，HO-1 上调的斑块中的肌细胞会在血管空间周围自发重塑，形成充满非凝血血液的泵室。这些发现表明，成年心肌细胞可能比以前认为的具有更大的可塑性，并且通过优化，可能适合作为梗死修复和心脏组织工程的自体细胞来源。实验将研究临床相关的新策略，旨在应对当前使用自体成体心肌细胞的四个挑战：提高心肌细胞对缺血的耐受性；将贴片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 的转录激活剂将通过离体和静脉注射两种方式进行递送，测试一种新的透化剂作为改善药物递送至三维组织移植物中央细胞的方法。定时释放 bFGF 的水凝胶将与动员的网膜蒂一起应用，以促进与宿主脉管系统的整合，并产生高容量的心外血源来支持补片。将 HO-1 局部 AAV 基因递送至贴片将用于探索 HO-1 对间质纤维化的长期基质调节作用。最后，将评估补片肌纤维排列和收缩蛋白缺血重新编程对补片生物力学和心室功能的影响。该项目的一个独特之处是有机会在平行实验中使用心脏手术患者的人类心房组织替代小鼠组织作为供体来源。因此，实验策略将在未来可能受益于这项新技术的患者群体的组织中进行测试。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努力，共同努力实现具有预期早期临床适用性的重要治疗终点。与公共卫生的相关性：心脏病是美国的首要死因。心脏病发作后，心肌质量不可逆地丢失，通常导致心力衰竭。目前正在研究的替代失去肌肉的方法建议使用胚胎干细胞或尚未被证明可以转化为心肌的细胞类型。该项目研究了一种新颖但可能的可能性，即可以对患者心房中的消耗性心肌细胞进行改造，使其能够在移植到受损心室后存活下来，以预防和治疗心力衰竭。