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Human Myocardium Engineered Using Developmentally-Inspired Protein Scaffolds

使用受发育启发的蛋白质支架设计人类心肌

基本信息

批准号：
8355924
负责人：
Adam Walter Feinberg
金额：
$ 215.27万
依托单位：
CARNEGIE-MELLON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-19 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8355924
关键词：
3-Dimensional Acute Architecture Arrhythmia Biological Models Biomimetics Cardiac Cardiac Myocytes Cells Cessation of life Chick Embryo Chronic Congestive Heart Failure Cues Derivation procedure Development Developmental Biology Embryo Embryonic Development Engineering Event Extracellular Matrix Fibronectins Future Guided Tissue Regeneration Heart Human In Vitro Knowledge Mechanics Mitotic Molecular Structure Morphogenesis Muscle Myocardial Infarction Myocardium Natural regeneration Pathway interactions Process Proliferating Property Proteins Relative (related person)Scaffolding Protein Science Staging Stem cells Stroke Structure Techniques Testing Three-Dimensional Imaging Tissue Engineering Tissues Vascularization Work abstracting cardiogenesis design high risk improved in vivo induced pluripotent stem cell injured insight myogenesis public health relevance regenerative repaired scaffold stem tissue regeneration

项目摘要

DESCRIPTION (Provided by the applicant) Abstract: Myocardial infarction is a major cause of cardiac-related death in the US and those fortunate to survive the acute event suffer from chronic high 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 cardiomyocytes can be derived from embryonic stem (ES) and induced pluripotent stem (iPS) cells, as well as transdifferentiated from other cells. However, organizing these cardiomyocytes to approximate or mimic the 3-D structure of stereotypical vascularized myocardium is still a major and unresolved challenge. Tissue engineering seeks to use polymeric scaffolds to organize cardiomyocytes and other cells such that cell- cell and cell-matrix interactions in concert with soluble factors guide tissue regeneration. While this has proven effective at short-term regeneration of cardiomyocyte-rich muscle, vascularization of these constructs and long- term survival have been quite limited and needs to be improved. Cardiogenesis during embryonic development produces vascularized myocardium, but current regenerative strategies do not mimic the extracellular matrix (ECM) that surrounds the cells in terms of composition or nanofibrillar architecture, nor are the mechanical properties matched to the myogenesis process. We hypothesize that the ECM, and especially fibronectin, in the developing heart encodes cues for the specification, differentiation and organization of cells into myocardium and that developmentally-staged, engineered matrices can recapitulate these cues in vitro, enabling a synthetic developmental pathway to tissue regeneration. To achieve this we are combining developmental biology, advanced 3-D imaging, materials science and cardiac tissue engineering. By combining such complementary and cutting-edge expertise, we are confident that our studies will yield new insights to actively move the field forward. To test our hypothesis, we will analyze the ECM in vivo during heart development and use the knowledge we gain to develop new 3-D cardiac tissue engineering techniques by: 1) Identifying the 3-D composition and structure of fibronectin in the vertebrate embryo during cardiac morphogenesis. We will use the chick embryo as an experimentally tractable model system. 2) Applying the ECM as the design template to engineer 3-D protein matrices that recapitulate the key compositional and structural features required for cardiac morphogenesis. 3) Engineering biomimetic, 3-D ECM nanofibrillar scaffolds and regenerate human myocardium using induced pluripotent stem cells. We will quantitatively assess the structure, molecular expression and electromechanical function relative to the native heart. Public Health Relevance: Myocardial infarction is a major cause of cardiac-related death in the US because the cardiomyocytes that survive are unable to repair the injured heart. Recent advances in stem cells have enabled derivation of new cardiomyocytes in large numbers, but organizing these cells into 3-D muscle tissue remains an unresolved challenge. We will determine how proteins in the extracellular matrix of the developing vertebrate heart guide cardiac morphogenesis and use that as the design template to engineer biomimetic protein scaffolds. This will enable us to tissue engineering 3-D human cardiac tissues, which will have future application in heart repair.

描述（由申请人提供）摘要：心肌梗死是美国心脏相关死亡的主要原因，那些幸运地在急性事件中幸存下来的人患有心律失常、中风和充血性心力衰竭的慢性高风险。修复心脏是困难的，因为心肌细胞是有丝分裂后，不能增殖，以再生受损组织。最近的研究表明，心肌细胞可以来源于胚胎干细胞（ES）和诱导多能干细胞（iPS），也可以从其他细胞转分化。然而，组织这些心肌细胞近似或模仿的3-D结构的刻板血管化心肌仍然是一个重大的和未解决的挑战。组织工程试图使用聚合物支架来组织心肌细胞和其他细胞，使得细胞-细胞和细胞-基质相互作用与可溶性因子一起引导组织再生。虽然这已被证明对富含心肌细胞的肌肉的短期再生有效，但这些构建体的血管化和长期存活已经相当有限，需要改进。胚胎发育期间的心脏发生产生血管化心肌，但目前的再生策略并不模拟围绕细胞的细胞外基质（ECM）的组成或纳米纤维结构，也没有与肌发生过程相匹配的机械性能。我们假设，在发育中的心脏中，ECM，尤其是纤连蛋白，编码细胞的特化、分化和组织的线索，心肌和发育阶段的工程基质可以在体外重现这些线索，从而实现组织再生的合成发育途径。为了实现这一目标，我们结合了发育生物学，先进的3D成像，材料科学和心脏组织工程。通过结合这种互补和尖端的专业知识，我们相信我们的研究将产生新的见解，积极推动该领域的发展。为了验证我们的假设，我们将在体内分析心脏发育过程中的ECM，并利用我们获得的知识开发新的三维心脏组织工程技术：1）确定心脏形态发生过程中脊椎动物胚胎中纤维连接蛋白的三维组成和结构。我们将使用鸡胚作为实验上易处理的模型系统。2)应用ECM作为设计模板来工程化3-D蛋白质基质，其概括了心脏形态发生所需的关键组成和结构特征。3)工程仿生，3-D ECM纳米纤维支架和再生人类心肌使用诱导多能干细胞。我们将定量评估相对于天然心脏的结构，分子表达和机电功能。公共卫生相关性：心肌梗死是美国心脏相关死亡的主要原因，因为存活的心肌细胞无法修复受损的心脏。干细胞的最新进展已经能够大量衍生出新的心肌细胞，但将这些细胞组织成3D肌肉组织仍然是一个尚未解决的挑战。我们将确定发育中的脊椎动物心脏细胞外基质中的蛋白质如何指导心脏形态发生，并将其用作设计模板来设计仿生蛋白质支架。这将使我们能够组织工程三维人体心脏组织，这将在心脏修复中有未来的应用。