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

超过9%的美国人患有糖尿病，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，用于恢复胰岛素生成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提供了一个答案，但仍有许多挑战阻碍了这些细胞的产生。通过实验和计算模型，该项目正在系统地开发一种改进的生物制造系统，该系统将以更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为高中生举办的暑期工作坊，以实验室研究为特色，以及与干细胞制造相关的讲座。在这个跨学科项目中，正在设计一个过程，使用自动搅拌悬浮生物反应器培养将人类多能干细胞（hPSCs）转化为功能性β细胞，并进一步成熟为增强β细胞（eBCs）。基于种群平衡方程的计算模型正与生物反应器实验相结合，以系统合理的方式筛选和选择条件，以较低的成本获得最佳的β细胞产量。生物制造过程的效率和可重复性是这一过程工程方法的关键目标。具体而言，以下具体目标正在追求：1)在搅拌悬浮生物反应器中将hPSCs分化为未成熟的β细胞；2)在生物反应器培养中诱导hpsc来源的β细胞成熟为功能性eBCs；3)从人造血干细胞中产生β细胞，并在完全自动化的生物过程中将其成熟为eBCs。定量模型的使用将导致hPSC分化和生物处理的基于规则的设计，并且与药物开发中的质量设计概念兼容。

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.