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

doi:10.1016/j.stem.2023.11.010

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	127-147.e9
Journal	Cell Stem Cell
Volume	31
Issue number	1
DOIs	https://doi.org/10.1016/j.stem.2023.11.010
Publication status	Published - 4 Jan 2024

Keywords

bovine
developmental potential
engineered transcription factor
human
iPSC
mouse
naive pluripotency
non-human primate
Oct4
porcine
POU linker
reprogramming
reset
Sox17
Sox2
Sox2/Oct4 heterodimer structure
super-SOX
tetraploid complementation

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1-s2.0-S1934590923004022-mainFinal published version, 8.26 MBLicence: CC BY

Cite this

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title = "Highly cooperative chimeric super-SOX induces naive pluripotency across species",

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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author = "MacCarthy, {Caitlin M.} and Guangming Wu and Vikas Malik and Yotam Menuchin-Lasowski and Taras Velychko and Gal Keshet and Rui Fan and Ivan Bedzhov and Church, {George M.} and Ralf Jauch and Vlad Cojocaru and Sch{\"o}ler, {Hans R.} and Sergiy Velychko",

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AU - Keshet, Gal

AU - Fan, Rui

AU - Bedzhov, Ivan

AU - Church, George M.

AU - Jauch, Ralf

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AU - Schöler, Hans R.

AU - Velychko, Sergiy

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Highly cooperative chimeric super-SOX induces naive pluripotency across species

Abstract

Keywords

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