幹細胞ノアの方舟(Stem cell Noah’s Ark)

2023-12-23

2023-12-22 マックス・プランク研究所

◆ドイツのマックス・プランク分子生物医学研究所の研究者らが率いる国際研究チームが、新しい再プログラム因子「super-Sox」を開発し、Oct4との協力能力を向上させ、高品質な誘導多能性幹細胞(iPS細胞)の生成を実現しました。
◆super-Soxを用いることで、ヒトやマウス、サル、牛、ブタなどの異なる種から効率的にiPS細胞を生成できるようになり、再生医療や臓器移植の可能性が拡大し、絶滅危惧種の保存などにも応用が期待されています。

<関連情報>

キメラSuper-SOXが種を超えてナイーブな多能性を誘導することを発見 Highly cooperative chimeric super-SOX induces naive pluripotency across species

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
Cell Stem Cell Published: December 22, 2023
DOI:https://doi.org/10.1016/j.stem.2023.11.010

Highlights

•Yamanaka cocktail upgraded with Sox2-17 enhanced iPSC generation in 5 species
•Sox2^A61→V swap at Sox2/Oct4 interface improves the quality of OSKM iPSCs
•Sox2/Oct4 dimer is the master regulator of high-quality naive pluripotency
•Naive reset using episomal SK boosts the developmental potential of PSCs across species

Summary

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.