Reduced MEK Inhibition Preserves Genomic Stability in Naive Human Embryonic Stem Cells

Overview

Journal Nat Methods

Specialties Biomedical Engineering
Pathology

Date 2018 Aug 22

PMID 30127506

Citations 51

Authors

Bruno Di Stefano

Mai Ueda

Shan Sabri

Justin Brumbaugh

Aaron J Huebner

Anna Sahakyan

Kendell Clement

Katie J Clowers

Alison R Erickson

Keiko Shioda

Steven P Gygi

Hongcang Gu

Toshi Shioda

Alexander Meissner

Yasuhiro Takashima

Kathrin Plath

Konrad Hochedlinger

Affiliations

Soon will be listed here.

Abstract

Human embryonic stem cells (hESCs) can be captured in a primed state in which they resemble the postimplantation epiblast, or in a naive state where they resemble the preimplantation epiblast. Naive-cell-specific culture conditions allow the study of preimplantation development ex vivo but reportedly lead to chromosomal abnormalities, which compromises their utility in research and potential therapeutic applications. Although MEK inhibition is essential for the naive state, here we show that reduced MEK inhibition facilitated the establishment and maintenance of naive hESCs that retained naive-cell-specific features, including global DNA hypomethylation, HERVK expression, and two active X chromosomes. We further show that hESCs cultured under these modified conditions proliferated more rapidly; accrued fewer chromosomal abnormalities; and displayed changes in the phosphorylation levels of MAPK components, regulators of DNA damage/repair, and cell cycle. We thus provide a simple modification to current methods that can enable robust growth and reduced genomic instability in naive hESCs.

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