Collaborative Research: Bioprocess development for the generation of functional pancreatic islet cells from human pluripotent stem cells

合作研究：从人类多能干细胞生成功能性胰岛细胞的生物工艺开发

• 批准号: 1743367
• 负责人: Emmanouhl Tzanakakis
• 金额: $ 42万
• 依托单位: Tufts University
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1743367&HistoricalAwards=false
• 关键词: Collaborative; Research; Bioprocess; development; generation

More than 9% of the US population suffers from diabetes, and the associated healthcare costs are among the highest of the major diseases. There is currently no cure for diabetes, and treatment to control blood sugar entails frequent insulin injections but does not prevent long-term complications such as blindness and heart disease. Pancreatic cell transplantation to restore the production of insulin is severely limited by the scarcity of donor tissue. Converting stem cells to insulin-producing cells may provide an answer, but there are still many challenges that prevent the production of sufficient numbers of these cells. Using experiments and computational modeling, this project is systematically developing an improved biomanufacturing system that will increase the production rate of pancreatic cells while at a lower cost. The planned work is providing interdisciplinary training for undergraduate and graduate students in STEM fields with an emphasis on biomanufacturing. Educational and outreach activities include summer workshops for high school students, featuring laboratory research, and lectures relevant to stem cell manufacturing.In this interdisciplinary project, a process is being engineered using automated stirred-suspension bioreactor cultivation for the conversion of human pluripotent stem cells (hPSCs) to functional beta-cells and further maturation to enhanced beta-cells (eBCs). Computational modeling, based on population balance equations, is being combined with bioreactor experimentation to screen and select conditions in a systematic and rational fashion for optimal beta-cell yields with lower costs. Efficiency and reproducibility in the biomanufacturing process are key goals in this process engineering approach. In particular, the following specific aims are being pursued: 1) differentiating hPSCs to immature beta-cells in stirred suspension bioreactors; 2) inducing the maturation of hPSC-derived beta-cells to functional eBCs in bioreactor culture; and 3) producing beta-cells from hPSCs and driving their maturation to eBCs in a fully automated bioprocess. The utilization of quantitative models will result in a rule-based design for hPSC differentiation and bioprocessing and is compatible with quality-by-design concepts in pharmaceutical development.

超过9%的美国人口患有糖尿病，相关的医疗费用是主要疾病中最高的。目前还没有治愈糖尿病的方法，控制血糖的治疗需要频繁注射胰岛素，但不能预防失明和心脏病等长期并发症。由于供体组织的稀缺，恢复胰岛素产生的胰腺细胞移植受到严重限制。将干细胞转化为产生胰岛素的细胞可能会提供一个答案，但仍然存在许多挑战，阻止产生足够数量的这些细胞。通过实验和计算建模，该项目正在系统地开发一种改进的生物制造系统，该系统将以较低的成本提高胰腺细胞的生产率。计划的工作是为STEM领域的本科生和研究生提供跨学科培训，重点是生物制造。教育和推广活动包括针对高中生的暑期讲习班，以实验室研究为特色，以及与干细胞制造相关的讲座。在这一跨学科项目中，正在设计一种使用自动搅拌悬浮生物反应器培养将人类多能干细胞（hPSC）转化为功能性β细胞并进一步成熟为增强型β细胞（eBCs）的过程。基于群体平衡方程的计算建模正与生物反应器实验相结合，以系统和合理的方式筛选和选择条件，以获得成本较低的最佳β细胞产量。生物制造过程中的效率和再现性是这种过程工程方法的关键目标。具体而言，正在追求以下具体目标：1）在搅拌悬浮生物反应器中将hPSC分化为未成熟的β细胞; 2）在生物反应器培养物中诱导hPSC衍生的β细胞成熟为功能性eBCs;以及3）在全自动生物过程中从hPSC产生β细胞并驱动其成熟为eBCs。定量模型的利用将导致基于规则的hPSC分化和生物加工设计，并且与药物开发中的质量设计概念相容。

项目成果

MicroRNA-7 directly targets Reg1 in pancreatic cells

• DOI: 10.1152/ajpcell.00013.2019
• 发表时间: 2019-08-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
• 影响因子: 5.5
• 作者: Downing, Shawna;Zhang, Fan;Tzanakakis, Emmanuel S.
• 通讯作者: Tzanakakis, Emmanuel S.

Non‐xenogeneic expansion and definitive endoderm differentiation of human pluripotent stem cells in an automated bioreactor

自动化生物反应器中人多能干细胞的非异种扩增和定形内胚层分化

• DOI: 10.1002/bit.27629
• 发表时间: 2020
• 期刊: Biotechnology and Bioengineering
• 影响因子: 3.8
• 作者: Jacobson, Elena F.;Chen, Zijing;Stoukides, Demetrios M.;Nair, Gopika G.;Hebrok, Matthias;Tzanakakis, Emmanuel S.
• 通讯作者: Tzanakakis, Emmanuel S.