UNS: Development of a Micropost Approach for the Contractile Maturation of iPS-Derived Cardiomyocytes

UNS：开发用于 iPS 衍生心肌细胞收缩成熟的微柱方法

• 批准号: 1509106
• 负责人: Nathan Sniadecki
• 金额: $ 45万
• 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: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1509106&HistoricalAwards=false
• 关键词: UNS; Development; Micropost; Approach; Contractile

PI: Sniadecki, Nathan J. Proposal Number: 1509106The goal of this project is to develop a novel strategy that improves the functionality of cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) in culture. Human induced pluripotent stem cells are not harvested from embryos, which means they can serve as a noncontroversial and plentiful source of cardiomyocytes. These cells have the potential to be used to reverse the damage to cardiac tissue caused by heart attacks, assess new pharmacological treatments for heart disease, and serve as a model system for studying heart development. To unlock the potential of hiPSC-CMs, this project will evaluate the effects of mechanical cues like substrate stiffness, cell shape, cyclic strain, and cell-cell contact in combination with biochemical treatments that promote cardiac maturation. The expected outcome of this project is an effective approach for in vitro culture of hiPSC-CMs that can be widely adopted.The lack the contractile power and maturation markers for hiPSC-CMs is a major challenge to overcome in order for these cells to be used effectively as a source of new cardiomyocytes. To address this challenge, the efforts in this project are centered on using arrays of flexible microposts for evaluating the contractile forces of hiPSC-CMs and quantitative fluorescence microscopy techniques to assess their myofibril structure, hypertrophy, isoform expression, and calcium handling. Tasks 1 and 2 of this project focus on studying the mechanical cues that improve the contractility and maturation of hiPSC-CMs, including cell alignment, cell-cell contact, extracellular stiffness, and applied strain. Task 3 examines the effectiveness of these mechanical cues alongside biochemical treatments that are related to cardiac development. The broader impacts of this work lie in the potential advancement of new cardiac therapies, drug screening, and developmental studies. In addition, the project has educational and outreach components that will impact the training and career development of future engineers who will work at the interface between engineering, cardiology, and developmental biology.

PI：Sniadecki，Nathan J. 提案编号：1509106本项目的目标是开发一种新的策略，改善培养中人诱导多能干细胞（hiPSC-CM）衍生的心肌细胞的功能。人类诱导多能干细胞不是从胚胎中获得的，这意味着它们可以作为心肌细胞的无争议和丰富的来源。 这些细胞有可能用于逆转心脏病发作对心脏组织造成的损伤，评估心脏病的新药物治疗，并作为研究心脏发育的模型系统。 为了释放hiPSC-CM的潜力，该项目将评估机械线索的影响，如基底硬度，细胞形状，循环应变和细胞-细胞接触，结合促进心脏成熟的生化治疗。本项目的预期成果是为hiPSC-CMs的体外培养提供一种可广泛采用的有效方法。hiPSC-CMs缺乏收缩能力和成熟标志物是一个主要挑战，为了使这些细胞有效地用作新心肌细胞的来源，需要克服。为了应对这一挑战，该项目的努力集中在使用柔性微柱阵列来评估hiPSC-CM的收缩力和定量荧光显微镜技术来评估其肌原纤维结构、肥大、同种型表达和钙处理。 该项目的任务1和任务2重点研究改善hiPSC-CM收缩性和成熟的机械因素，包括细胞排列、细胞间接触、细胞外刚度和施加的应变。任务3检查这些机械线索以及与心脏发育相关的生化治疗的有效性。 这项工作的更广泛影响在于新的心脏治疗，药物筛选和开发研究的潜在进步。 此外，该项目具有教育和推广组件，将影响未来工程师的培训和职业发展，他们将在工程，心脏病学和发育生物学之间的接口工作。

项目成果

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