ECM Shrink Wrapped Human Cardiomyocytes and Endothelial Cells to Accelerate Myocardial Regeneration

ECM 收缩包裹人心肌细胞和内皮细胞以加速心肌再生

基本信息

批准号：
9924688
负责人：
Adam Walter Feinberg
金额：
$ 17.67万
依托单位：
CARNEGIE-MELLON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924688
关键词：
3-Dimensional Action Potentials Acute Address Alginates Animal Model Architecture Arrhythmia Autologous Basal lamina Biological Models Biomimetics Blood Vessels Calcium Caliber Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cause of Death Cell Survival Cell Therapy Cell membrane Cell-Cell Adhesion Cells Cessation of life Chronic Clinical Treatment Collagen Collagen Type IV Confocal Microscopy Congestive Heart Failure Corneal Endothelium Coupling Cytoskeleton EFRAC Embryo Endothelial Cells Engineering Environment Event Extracellular Matrix Extracellular Matrix Proteins Eye Fibrin Fibroblasts Fibronectins Frequencies Future Gap Junctions Gel Gene Expression Goals Growth Growth Factor Heart Heart Diseases Heart Injuries Heart failure Human In Vitro Individual Injectable Injections Instruction Integrin Binding Laminin Mechanics Mitotic Morbidity - disease rate Muscle Muscle satellite cell Myocardial Myocardial Infarction Myocardium Nanostructures Natural regeneration Patients Performance Population Positioning Attribute Process Proliferating Proteins Risk Rodent Model Role Seminal Shapes Source Stroke Structure Surface Techniques Technology Therapeutic Thick Tissue Engineering Tissues Vascularization Work angiogenesis base cardiac regeneration cardiac repair clinical application clinically relevant cost density embryonic stem cell experimental study human embryonic stem cell improved in vitro Model in vivo in vivo regeneration induced pluripotent stem cell innovation matrigel mechanotransduction mortality multiphoton microscopy myogenesis nano nanoengineering nanofabrication nonhuman primate novel novel strategies paracrine regenerative therapy repaired scaffold stem stem cells tissue regeneration transdifferentiation

项目摘要

Myocardial infarction (MI) is a major cause of cardiac-related death in the US and those fortunate to survive the acute event suffer from chronic risk of arrhythmia, stroke and congestive heart failure. Repairing the heart is difficult because cardiomyocytes are post-mitotic and cannot proliferate in order to regenerate damaged tissue. Recent work has demonstrated that human cardiomyocytes can be derived from embryonic stem (ES) and induced pluripotent stem (iPS) cells, as well as transdifferentiated from other cells. However, survival and functional integration of these cardiomyocytes into stereotypical vascularized myocardium is still a major and unresolved challenge. This proposal describes a breakthrough towards therapeutic cell delivery by wrapping each cell in a nanostructured extracellular matrix (ECM) scaffold tailor made for enhancing survival, myogenesis and integration into infarcted myocardium. The key innovation in our approach is the ability to engineer 50-100 nm thick sheets of ECM with defined protein composition and shape and wrap this around individual cells or small cell ensembles. This is an improvement over current encapsulation technology because we can build the ECM around cardiomyocytes and endothelial cells to mimic the ECM that naturally surrounds these cells in the healthy heart. This is critical, because the ECM is a primary regulator of integrin binding, growth factor sequestration and mechanotransduction. Our preliminary results demonstrate that our novel surface-initiated assembly technique can build an ECM nano-scaffold from a range of matrix proteins and shrink wrap cardiomyocytes and endothelials cells. Further, we have shown using corneal endothelial cells that we can effectively delivery cells in vivo. This proposal will build upon these results by achieving three primary aims. One, develop the ECM nano-scaffold technology to shrink wrap cardiomyocytes and endothelial cells in engineered layers of fibronectin, laminin and collagen type IV that match the matrix in the native myocardium. Two, interrogate the role of ECM nano-scaffold composition, size and cell population on maximizing muscle formation, pre-vascularization and contractility in 3D tissue. Looking forward, achieving these aims will result in an injectable cell delivery technology that has enhanced capability to promote the retention, survival, integration, myogenesis and vascularization of cardiomyocytes and endothelial cells into the injured heart. This would have profound consequences by leading towards clinically-relevant therapeutic strategies to decrease morbidity and mortality in MI and cardiovascular disease patients

心肌梗死 (MI) 是美国心脏相关死亡的主要原因，也是那些幸运幸存的人的主要原因急性事件有发生心律失常、中风和充血性心力衰竭的慢性风险。修复心脏就是困难是因为心肌细胞处于有丝分裂后并且不能增殖以再生受损组织。最近的研究表明，人类心肌细胞可以来源于胚胎干细胞（ES）和诱导多能干（iPS）细胞，以及从其他细胞转分化的细胞。然而，生存和这些心肌细胞与典型的血管化心肌的功能整合仍然是一个主要和未解决的挑战。该提案描述了通过包裹治疗细胞递送的突破纳米结构细胞外基质（ECM）支架中的每个细胞都是为提高存活率而定制的，肌发生和整合到梗塞心肌中。我们方法的关键创新是能够设计 50-100 nm 厚的 ECM 片，具有确定的蛋白质成分和形状，并将其包裹起来单个细胞或小细胞群。这是对当前封装技术的改进因为我们可以在心肌细胞和内皮细胞周围构建 ECM，以模仿自然形成的 ECM 围绕着健康心脏中的这些细胞。这很重要，因为 ECM 是整合素的主要调节因子结合、生长因子隔离和机械转导。我们的初步结果表明，我们的新型表面引发组装技术可以从一系列基质蛋白构建 ECM 纳米支架以及收缩包装心肌细胞和内皮细胞。此外，我们还展示了使用角膜内皮细胞我们可以在体内有效地输送细胞。该提案将以这些成果为基础，通过实现三个目标主要目标。一、开发ECM纳米支架技术收缩包裹心肌细胞和内皮细胞纤连蛋白、层粘连蛋白和 IV 型胶原工程层中的细胞与天然基质相匹配心肌。二、探究ECM纳米支架的组成、大小和细胞群对细胞外基质的作用最大限度地提高 3D 组织中的肌肉形成、预血管化和收缩性。展望未来，实现目标这些目标将带来一种可注射细胞输送技术，该技术具有增强促进心肌细胞和内皮细胞的保留、存活、整合、肌生成和血管化进入受伤的心。这将通过导致临床相关的治疗产生深远的影响降低心肌梗死和心血管疾病患者发病率和死亡率的策略