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Understanding the Role of Fluidic Microenvironment in Stem Cell Suspension Culture toward Scalable Biomanufacturing

了解流体微环境在干细胞悬浮培养中对可扩展生物制造的作用

基本信息

批准号：
1707190
负责人：
Hideaki Tsutsui
金额：
$ 39.98万
依托单位：
University of California-Riverside
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：
2017-09-01 至 2023-03-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1707190&HistoricalAwards=false
关键词：
Understanding Role Fluidic Microenvironment Stem

项目摘要

Human pluripotent stem cells (hPSCs) and cells that differentiate from these are anticipated to be in great demand for cell-based therapies and engineered tissues. In order to meet this demand, these cells need to be made available in sufficient number to supply both laboratories and, in the future, treating physicians. Therefore, they actually need to be manufactured. Three-dimensional (3D) stirred suspension culture, due to its scalability and ease of automation, is a promising platform for meeting such a demand, while potentially reducing the cost of production significantly. However, culturing undifferentiated hPSCs using this technique is a relatively new development in the past several years, and little is known about the role of the fluid environment and stirring process on the cells? expression of various traits. This research will investigate the effect of shear forces applied through the fluid environment on the cells, including their gene expression, differentiation, and survival. The new discoveries and tools anticipated from this study are expected to be applicable to studies of other medically relevant cell types, such as neurospheres, pancreatic islets, and adult stem cells, potentially addressing the existing bottlenecks that reduce the efficiency of their current production. In conjunction with the outlined research activities, the project will develop and integrate several outreach and educational activities, including: developing new crosscutting course materials for stem cell biology and mechanical engineering courses; recruiting and mentoring both undergraduate and graduate students, particularly women and underrepresented minorities, in cutting-edge research; and engaging local K-12 teachers and students through outreach efforts.The current research aims to address a critical knowledge gap relevant to stem cell biomanufacturing, by undertaking three tasks: 1) determining the roles of fluidic shear on growing stem cell aggregates; 2) identifying biomolecular mechanisms of shear-induced mechanotransduction; and 3) designing and verifying a suspension culture that will impose uniform shear on the stem cells. Expected outcomes of this research effort include 1) quantitative correlations between shear stress, aggregate size, and cell fates, 2) molecular pathway models for shear-controlled mechanotransduction, and 3) new means to apply and quantify homogeneous shear stress inputs to the stem cells and their aggregates. Collectively, these outcomes are expected to enable a novel approach to expand and differentiate stem cells using the fluidic microenvironment (e.g., fluid shear) as a critical input parameter.

预计人类多能干细胞（hPSC）和从这些细胞分化的细胞对基于细胞的疗法和工程组织的需求很大。为了满足这一需求，需要提供足够数量的细胞，以供应实验室和未来的治疗医生。因此，实际上需要制造。三维（3D）搅拌悬浮培养，由于其可扩展性和易于自动化，是一个有前途的平台，以满足这样的需求，同时可能降低生产成本显着。然而，使用这种技术培养未分化的hPSC是过去几年中相对较新的发展，并且对流体环境和搅拌过程对细胞的作用知之甚少。各种特征的表达。这项研究将研究通过流体环境施加的剪切力对细胞的影响，包括它们的基因表达，分化和存活。预计这项研究的新发现和工具将适用于其他医学相关细胞类型的研究，如神经球，胰岛和成体干细胞，可能会解决降低其当前生产效率的现有瓶颈。结合概述的研究活动，该项目将开发和整合多项外展和教育活动，包括：开发干细胞生物学和机械工程课程的新交叉课程材料;招募和指导本科生和研究生，特别是女性和代表性不足的少数族裔，从事前沿研究;目前的研究旨在解决干细胞生物制造相关的关键知识缺口，通过三项任务：1）确定流体剪切对生长干细胞聚集体的作用; 2）鉴定剪切诱导的机械转导的生物分子机制;和3）设计和验证将对干细胞施加均匀剪切的悬浮培养物。这项研究工作的预期成果包括1）剪切应力，聚集体大小和细胞命运之间的定量相关性，2）剪切控制机械转导的分子途径模型，以及3）将均匀剪切应力输入应用于干细胞及其聚集体并对其进行量化的新方法。总的来说，这些结果有望实现一种使用流体微环境（例如，流体剪切）作为关键输入参数。