{"doi":"10.1016/j.celrep.2021.109233","title":"Probing the signaling requirements for naive human pluripotency by high-throughput chemical screening","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.","journal":"Cell Reports","year":2021,"id":153723,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":67,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9528,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":233611,"name":"Kyoung‐mi Park","orcid":"0000-0001-7548-8432","position":1,"is_corresponding":false},{"id":233609,"name":"Laura A. Fischer","orcid":"0000-0002-9548-3441","position":2,"is_corresponding":false},{"id":233607,"name":"Chen Dong","orcid":"0000-0002-5405-5715","position":3,"is_corresponding":false},{"id":248410,"name":"Tenzin Lungjangwa","orcid":null,"position":4,"is_corresponding":false},{"id":652687,"name":"Marta Jiménez","orcid":null,"position":5,"is_corresponding":false},{"id":492997,"name":"Dominick Casalena","orcid":null,"position":6,"is_corresponding":false},{"id":652688,"name":"Brian Chew","orcid":null,"position":7,"is_corresponding":false},{"id":45538,"name":"Sabine Dietmann","orcid":"0000-0001-6672-8457","position":8,"is_corresponding":false},{"id":491949,"name":"Douglas S. Auld","orcid":"0000-0002-8164-9375","position":9,"is_corresponding":false},{"id":30028,"name":"Rudolf Jaenisch","orcid":"0000-0002-2540-7099","position":10,"is_corresponding":false},{"id":233616,"name":"Thorold W. Theunissen","orcid":"0000-0001-6943-7858","position":11,"is_corresponding":false},{"id":233610,"name":"Shafqat Ali Khan","orcid":"0000-0002-8573-792X","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-18T23:43:44.759273Z","pmid":"34133938","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}