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

PI: Sniadecki, Nathan J.提案号：1509106本项目的目标是开发一种新的策略，提高人类诱导多能干细胞（hiPSC-CMs）培养的心肌细胞的功能。人类诱导多能干细胞不是从胚胎中获取的，这意味着它们可以作为心肌细胞的一种无争议的丰富来源。这些细胞有潜力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-CMs的潜力，该项目将评估诸如底物刚度、细胞形状、循环应变和细胞-细胞接触等机械因素的影响，并结合促进心脏成熟的生化处理。本项目的预期结果为hiPSC-CMs体外培养提供了一种有效的方法，可广泛应用。为了使这些细胞有效地用作新心肌细胞的来源，hiPSC-CMs缺乏收缩能力和成熟标记是需要克服的主要挑战。为了应对这一挑战，本项目的工作集中在使用柔性微柱阵列来评估hiPSC-CMs的收缩力，并使用定量荧光显微镜技术来评估其肌原纤维结构、肥大、异构体表达和钙处理。本项目的任务1和任务2侧重于研究提高hiPSC-CMs的收缩性和成熟度的机械线索，包括细胞排列、细胞间接触、细胞外刚度和施加应变。任务3检查这些机械提示以及与心脏发育相关的生化治疗的有效性。这项工作的更广泛的影响在于新的心脏治疗，药物筛选和发展研究的潜在进展。此外，该项目还具有教育和推广内容，这将影响未来工程师的培训和职业发展，这些工程师将在工程、心脏病学和发育生物学之间的界面工作。

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.