{"doi":"10.3389/fimmu.2025.1675823","title":"Disruption of Notch signaling by KGF induces a developmental pause in thymocytes","abstract":"Keratinocyte growth factor (KGF) has been proposed as a therapeutic adjuvant to enhance T cell immune reconstitution, particularly following stem cell transplantation. Here, we demonstrate that the long-term KGF-induced increase in thymic cellularity and thymocyte differentiation is preceded by a transient developmental block prior to the β-selection checkpoint, observed as early as day 2 following KGF treatment. This early block is characterized by an increased expansion of uncommitted thymocytes and is driven by KGF-induced alterations in both cortical and medullary thymic epithelial cells (TECs). KGF suppresses Wnt/β-catenin signaling by downregulating distinct Wnt ligands in cTECs and mTECs, leading to reduced expression of FOXN1, a master regulator of TEC differentiation. Consequently, expression of Foxn1 -dependent genes, including Dll4 , a key Notch ligand required for early thymocyte development, is diminished. These findings reveal a novel mechanism of KGF action: an initial disruption of TEC-mediated signaling that transiently impairs early thymocyte differentiation, followed by enhanced proliferation and long-term thymic recovery.","journal":"Frontiers in Immunology","year":2025,"id":529376,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9616,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1146790,"name":"Francis A. Flomerfelt","orcid":"0000-0003-3422-606X","position":1,"is_corresponding":false},{"id":1290561,"name":"Ping Xue","orcid":"0000-0003-3935-4845","position":2,"is_corresponding":false},{"id":1408649,"name":"Anjali Chandroth","orcid":null,"position":3,"is_corresponding":false},{"id":248403,"name":"Constance Tom Noguchi","orcid":null,"position":4,"is_corresponding":false},{"id":1408163,"name":"Nikolaos Svoronos","orcid":"0000-0003-2556-3793","position":5,"is_corresponding":false},{"id":233605,"name":"Ronald E. Gress","orcid":"0000-0001-8259-5332","position":6,"is_corresponding":false},{"id":113313,"name":"Naomi Taylor","orcid":"0000-0002-2459-4558","position":7,"is_corresponding":false},{"id":1408648,"name":"Ruifeng Teng","orcid":null,"position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T02:50:56.971987Z","pmid":"41357235","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":[]}