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GMP-compliant iPS cell lines show widespread plasticity in a new set of differentiation workflows for cell replacement and cancer immunotherapy

诱导多能干细胞 重编程 细胞培养 间充质干细胞 间质细胞 细胞分化 细胞疗法 生物 细胞生物学 细胞 干细胞 计算生物学 计算机科学 癌症研究 胚胎干细胞 遗传学 基因
作者
Daniel Terheyden-Keighley,Melanie Hühne,Thomas G. Berger,Björn Hiller,Soraia Martins,Anna Gamerschlag,Davood Sabour,Andrea Meffert,Andreas Kislat,Carsten Slotta,François Hafezi,Jens Lichte,Smita Sudheer,Karen Tessmer,Katherina Psathaki,Marius Ader,Gesine Kögler,Boris Greber
出处
期刊:Stem Cells Translational Medicine [Wiley]
卷期号:13 (9): 898-911 被引量:2
标识
DOI:10.1093/stcltm/szae047
摘要

Abstract Cell therapeutic applications based on induced pluripotent stem cells (iPSCs) appear highly promising and challenging at the same time. Good manufacturing practice (GMP) regulations impose necessary yet demanding requirements for quality and consistency when manufacturing iPSCs and their differentiated progeny. Given the scarcity of accessible GMP iPSC lines, we have established a corresponding production workflow to generate the first set of compliant cell banks. Hence, these lines met a comprehensive set of release specifications and, for instance, displayed a low overall mutation load reflecting their neonatal origin, cord blood. Based on these iPSC lines, we have furthermore developed a set of GMP-compatible workflows enabling improved gene targeting at strongly enhanced efficiencies and directed differentiation into critical cell types: A new protocol for the generation of retinal pigment epithelium (RPE) features a high degree of simplicity and efficiency. Mesenchymal stromal cells (MSCs) derived from iPSCs displayed outstanding expansion capacity. A fully optimized cardiomyocyte differentiation protocol was characterized by a particularly high batch-to-batch consistency at purities above 95%. Finally, we introduce a universal immune cell induction platform that converts iPSCs into multipotent precursor cells. These hematopoietic precursors could selectively be stimulated to become macrophages, T cells, or natural killer (NK) cells. A switch in culture conditions upon NK-cell differentiation induced a several thousand-fold expansion, which opens up perspectives for upscaling this key cell type in a feeder cell-independent approach. Taken together, these cell lines and improved manipulation platforms will have broad utility in cell therapy as well as in basic research.
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