Evidence map›Paper›PMID 34133938›Full record

ArticleCell reports2021

Probing the signaling requirements for naive human pluripotency by high-throughput chemical screening.

Shafqat A Khan, Kyoung-Mi Park, Laura A Fischer, Chen Dong, Tenzin Lungjangwa, Marta Jimenez, Dominick Casalena, Brian Chew, Sabine Dietmann, Douglas S Auld and 2 more

Open access · goldAbstract read
In one paragraph

Article in Cell reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
42citing papers in PubMed, 2 pooled it
4.6field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

42 citing papers in PubMed, 2 syntheses or guidelines pooled it, 61 citations in OpenAlex.

  1. Pooled it
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  10. Mechanisms of human germ cell development.Nature reviews. Molecular cell biology · 2026
    Review
  11. Article
  12. Article
  13. H3K27ac Is Essential for Human Naive Pluripotency Modulated by m6A-Driven EP300 Expression.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025
    Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 4 institutions in 2 countries.

Shafqat A KhanDepartment of Developmental Biology and Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Kyoung-Mi ParkDepartment of Developmental Biology and Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Laura A FischerDepartment of Developmental Biology and Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Chen DongDepartment of Developmental Biology and Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Tenzin LungjangwaWhitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Marta JimenezNovartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
Dominick CasalenaNovartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
Brian ChewDepartment of Developmental Biology and Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Sabine DietmannDepartment of Developmental Biology and Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Douglas S AuldNovartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. Electronic address: douglas.auld@novartis.com.
Rudolf JaenischWhitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: jaenisch@wi.mit.edu.
Thorold W TheunissenDepartment of Developmental Biology and Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: t.theunissen@wustl.edu.
Washington University in St. Louis · USNovartis (United States) · USWhitehead Institute for Biomedical Research · USNovartis (China) · CN

Funding

Transcriptional condensates, epigenetic editing and Rett SyndromeR01MH104610 · NIMH · WHITEHEAD INSTITUTE FOR BIOMEDICAL RES · PI JAENISCH, RUDOLF, YOUNG, RICHARD · 2014 to 2023
$7.4M
Resolving epigenetic instability during pluripotent state transitions: a roadmap for exploiting the biomedical potential of dynamic human stem cell statesDP2GM137418 · NIGMS · WASHINGTON UNIVERSITY · PI THEUNISSEN, THOROLD · 2019 to 2019
$2.4M
NIGMS NIH HHS DP2 GM137418NIMH NIH HHS R01 MH104610
6 · The paper itself

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.

Indexed as

High-Throughput Screening AssaysSignal TransductionActivinsCells, CulturedEmbryo ImplantationHumansModels, BiologicalPluripotent Stem Cellsraf Kinasesactivin AActivinsraf KinasesDNA methylationFGFR signaling pathwayhigh-throughput screeningnaive pluripotencypre-implantation developmentprimed pluripotencysignal transductiontransposable elementstrophoblastX chromosome reactivation

Identifiers

PMID34133938
PMCPMC8272458
OpenAlexW3167699342

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.