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Probing the signaling requirements for naive human pluripotency by high-throughput chemical screening
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1-s2.0-S2211124721005921-main.pdf
Description
Published version
Size
6.1 MB
Format
Adobe PDF
Checksum (MD5)
e7356b06797c100e1fd4914754d61e1f
Author(s)
Khan, Shafqat A
Park, Kyoung-mi
Fischer, Laura A
Dong, Chen
Lungjangwa, Tenzin
Jimenez, Marta
Casalena, Dominick
Chew, Brian
Dietmann, Sabine
Auld, Douglas S
Date Issued
2021
Journal
Cell Reports
Publisher
Elsevier BV
Version
Final published version
Abstract
Naive human embryonic stem cells (hESCs) have been isolated that more closely resemble the pre-implantation epiblast compared to conventional "primed" hESCs, but the signaling principles underlying these discrete stem cell states remain incompletely understood. Here, we describe the results from a high-throughput screen using ∼3,000 well-annotated compounds to identify essential signaling requirements for naive human pluripotency. We report that MEK1/2 inhibitors can be replaced during maintenance of naive human pluripotency by inhibitors targeting either upstream (FGFR, RAF) or downstream (ERK1/2) kinases. Naive hESCs maintained under these alternative conditions display elevated levels of ERK phosphorylation but retain genome-wide DNA hypomethylation and a transcriptional identity of the pre-implantation epiblast. In contrast, dual inhibition of MEK and ERK promotes efficient primed-to-naive resetting in combination with PKC, ROCK, and TNKS inhibitors and activin A. This work demonstrates that induction and maintenance of naive human pluripotency are governed by distinct signaling requirements.
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
10.1016/j.celrep.2021.109233
