Highly cooperative chimeric super-SOX induces naive pluripotency across species

IF 19.8 1区医学 Q1 CELL & TISSUE ENGINEERING

Cell stem cell Pub Date : 2023-12-22 DOI:10.1016/j.stem.2023.11.010

Caitlin M. MacCarthy, Guangming Wu, Vikas Malik, Yotam Menuchin-Lasowski, Taras Velychko, Gal Keshet, Rui Fan, Ivan Bedzhov, George M. Church, Ralf Jauch, Vlad Cojocaru, Hans R. Schöler, Sergiy Velychko

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引用次数: 0

Abstract

Our understanding of pluripotency remains limited: iPSC generation has only been established for a few model species, pluripotent stem cell lines exhibit inconsistent developmental potential, and germline transmission has only been demonstrated for mice and rats. By swapping structural elements between Sox2 and Sox17, we built a chimeric super-SOX factor, Sox2-17, that enhanced iPSC generation in five tested species: mouse, human, cynomolgus monkey, cow, and pig. A swap of alanine to valine at the interface between Sox2 and Oct4 delivered a gain of function by stabilizing Sox2/Oct4 dimerization on DNA, enabling generation of high-quality OSKM iPSCs capable of supporting the development of healthy all-iPSC mice. Sox2/Oct4 dimerization emerged as the core driver of naive pluripotency with its levels diminished upon priming. Transient overexpression of the SK cocktail (Sox+Klf4) restored the dimerization and boosted the developmental potential of pluripotent stem cells across species, providing a universal method for naive reset in mammals.

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高度合作的嵌合超级SOX诱导跨物种的幼稚多能性

我们对多能性的了解仍然有限：iPSC 的生成只在少数模式物种中得到证实，多能干细胞系表现出不一致的发育潜能，种系传递只在小鼠和大鼠中得到证实。通过交换 Sox2 和 Sox17 之间的结构元素，我们构建了一种嵌合超级 Sox 因子 Sox2-17，它能增强小鼠、人类、猴、牛和猪这五种受测物种的 iPSC 生成。将 Sox2 和 Oct4 之间界面上的丙氨酸换成缬氨酸，可通过稳定 DNA 上的 Sox2/Oct4 二聚体实现功能增益，从而生成高质量的 OSKM iPSC，支持健康的全 iPSC 小鼠的发育。Sox2/Oct4二聚化是幼稚多能性的核心驱动力，其水平在启动时会降低。瞬时过表达SK鸡尾酒（Sox+Klf4）可恢复二聚化，提高多能干细胞在不同物种中的发育潜能，为哺乳动物的幼稚重置提供了一种通用方法。

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来源期刊

Cell stem cell 生物-细胞生物学

CiteScore

37.10

自引率

2.50%

发文量

151

审稿时长

42 days

期刊介绍： Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.