Mechanobiology of Engineered Heart Tissue

工程心脏组织的力学生物学

• 批准号: 1661730
• 负责人: Nathan Sniadecki
• 金额: $ 45.11万
• 依托单位: University of Washington
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1661730&HistoricalAwards=false
• 关键词: Mechanobiology; Engineered; Heart; Tissue

The overall goal of this project is to examine whether mechanical cues can improve the contractile function of engineered heart tissue (EHT) constructs. EHT constructs are made by tissue engineering approaches that use human cell derived cardiomyocytes. These constructs can serve as an ethical testbed for cardiology and pharmacology studies and can reduce the reliance on animal studies in some cases. EHT constructs are functional tissues for they produce muscle contractions that are visible in vitro. However, in the current state-of-the-art for EHT constructs, their contractility and physiology does not fully resemble that of adult heart tissue. As such, this project will subject EHT constructs to dynamically changing external loads in a novel bioreactor in order to build stronger muscle tissue through cardiac exercise. If successful, this project would achieve a "hearts-in-a-dish" platform for assessing new pharmacological treatments for heart disease, understanding inheritable myopathies, or studying the progression of cardiac pathologies. Research opportunities with this project will be provided to undergraduates and underrepresented minority groups. We will publicize our research to K-12 students at outreach events at the University of Washington to educate them on the innovations that are possible at the intersection of engineering and medicine.This project will provide a transformative approach to cardiac tissue engineering by magnetically measuring the biomechanical performance of EHT constructs and providing mechanobiological cues that drive their maturation towards adult levels. Real-time measurements of the contractile force and twitch frequency of EHT constructs will be achieved by growing the constructs on magnetic silicone posts, which deflect in portion to the applied force of the constructs. The motion of the magnetic posts will be measured using a novel array of magnetometers underneath a multi-well plate, which enable the EHT constructs to be monitored continually over a long period of time and in a parallel manner. Application of magnetic fields that pull on the magnetic posts will impart external forces on the EHT constructs to forcibly stretch the constructs before their contraction (preload) and forcibly restrain the constructs during a contraction (afterload). Application of fetal loading patterns of preload and afterload using magnetic forces will improve the myofibril structure, maturation markers, and contractile output of hPSC-CM in the EHT constructs through mechanobiological cues that replicate the increasing loads that the human heart experiences during fetal development. In broader terms, the approaches in this project are intended to mimic to the developmental loading patterns of preload and afterload in a developing human heart in order to improve the maturation of hPSC-CM grown in EHT constructs and assess the improvements by monitoring the contractile function of the cells.

本项目的总体目标是检查机械提示是否可以改善工程化心脏组织（EHT）结构的收缩功能。EHT构建体通过使用人细胞衍生的心肌细胞的组织工程方法制备。这些结构可以作为心脏病学和药理学研究的伦理试验平台，在某些情况下可以减少对动物研究的依赖。EHT构建体是功能性组织，因为它们产生体外可见的肌肉收缩。然而，在EHT结构的当前最新技术水平中，它们的收缩性和生理学并不完全类似于成人心脏组织。因此，该项目将使EHT结构在新型生物反应器中动态变化外部负荷，以便通过心脏运动建立更强大的肌肉组织。如果成功，该项目将实现一个“培养皿中的心脏”平台，用于评估心脏病的新药物治疗，了解遗传性肌病或研究心脏病理学的进展。 该项目的研究机会将提供给本科生和代表性不足的少数群体。我们将在华盛顿大学的外展活动中向K-12学生宣传我们的研究，教育他们在工程和医学的交叉点上可能实现的创新。该项目将通过磁性测量EHT结构的生物力学性能，并提供驱动其成熟到成人水平的机械生物学线索，为心脏组织工程提供一种变革性的方法。EHT结构的收缩力和抽搐频率的实时测量将通过在磁性硅胶柱上生长结构来实现，磁性硅胶柱部分偏转结构的施加力。将使用多孔板下方的新型磁力计阵列测量磁柱的运动，这使得能够在长时间内以并行方式连续监测EHT结构。施加磁场拉动磁柱将对EHT结构施加外力，以在收缩前强制拉伸结构（预加载），并在收缩期间强制约束结构（后加载）。使用磁力的前负荷和后负荷的胎儿负荷模式的应用将通过机械生物学线索改善EHT构建体中的hPSC-CM的肌原纤维结构、成熟标志物和收缩输出，所述机械生物学线索复制人类心脏在胎儿发育期间经历的增加的负荷。更广泛地说，本项目中的方法旨在模拟发育中的人类心脏中的前负荷和后负荷的发育负荷模式，以改善在EHT构建体中生长的hPSC-CM的成熟，并通过监测细胞的收缩功能来评估改善。

项目成果

A Rainbow Reporter Tracks Single Cells and Reveals Heterogeneous Cellular Dynamics among Pluripotent Stem Cells and Their Differentiated Derivatives

• DOI: 10.1016/j.stemcr.2020.06.005
• 发表时间: 2020-07-14
• 期刊: STEM CELL REPORTS
• 影响因子: 5.9
• 作者: El-Nachef, Danny;Shi, Kevin;Davis, Jennifer
• 通讯作者: Davis, Jennifer

Chromatin compartment dynamics in a haploinsufficient model of cardiac laminopathy

• DOI: 10.1083/jcb.201902117
• 发表时间: 2019-09-01
• 期刊: JOURNAL OF CELL BIOLOGY
• 影响因子: 7.8
• 作者: Bertero, Alessandro;Fields, Paul A.;Murry, Charles E.
• 通讯作者: Murry, Charles E.

Cronos Titin Is Expressed in Human Cardiomyocytes and Necessary for Normal Sarcomere Function

• DOI: 10.1161/circulationaha.119.039521
• 发表时间: 2019-11-12
• 期刊: CIRCULATION
• 影响因子: 37.8
• 作者: Zaunbrecher, Rebecca J.;Abel, Ashley N.;Murry, Charles E.
• 通讯作者: Murry, Charles E.

TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes

• DOI: 10.1038/s41467-019-12482-1
• 发表时间: 2019-10-11
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Miklas, Jason W.;Clark, Elisa;Ruohola-Baker, Hannele
• 通讯作者: Ruohola-Baker, Hannele