{"doi":"10.1101/2024.12.29.630675","title":"Organ injury accelerates stem cell differentiation by modulating a fate-transducing lateral inhibition circuit","abstract":"Abstract To rebuild tissue form and function, injured organs accelerate the differentiation of replacement stem cell progeny. Here we demonstrate that injury-induced factors open the throttle on faster differentiation by streamlining the archetypal signaling circuit that patterns cell fates. During normal turnover of the adult Drosophila intestine, fates are patterned by a conserved lateral inhibition circuit: In stem cell pairs, mutual activation of Notch receptor by Delta ligand feeds back to create opposing states of high Notch/low Delta and low Notch/high Delta; cells terminally differentiate once their Notch activity exceeds a fate-deciding threshold. After feeding flies a gut-damaging toxin, we perform in vivo imaging of real-time intestinal repair and trace Notch reporter dynamics in single cells. We find that tissue damage causes the speed of Notch signal activation to accelerate dramatically; faster activation expedites terminal differentiation by propelling cells past the critical Notch threshold more quickly. Combining single-cell analyses with dynamical modeling, we show that faster activation results from aberrant elevation of Delta ligand due to loss of time-delaying circuit feedback. Injury abolishes feedback via a cytokine-JAK-STAT relay from damaged cells to stem cells, causing stem cells to deactivate the Notch co-repressor that normally turns off Delta. Thus, organ injury unmasks latent plasticity in Notch-Delta lateral inhibition to propel the differentiation of new replacement cells. By unifying temporal and spatial fate control in a single, adaptable signaling circuit, organs tune stem cell dynamics to meet environmental challenges.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":508149,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":942076,"name":"Hsuan-Te Sun","orcid":"0000-0001-6421-4786","position":1,"is_corresponding":false},{"id":1174181,"name":"Saman Tabatabaee","orcid":"0009-0001-1332-3314","position":2,"is_corresponding":false},{"id":463803,"name":"Charles F. Lang","orcid":"0000-0001-6428-3941","position":3,"is_corresponding":false},{"id":1360198,"name":"Sebastian G. van Dijk","orcid":null,"position":4,"is_corresponding":false},{"id":463564,"name":"Yu‐Han Su","orcid":"0000-0002-6035-9395","position":5,"is_corresponding":false},{"id":1360199,"name":"Andrew Labofl","orcid":null,"position":6,"is_corresponding":false},{"id":1360200,"name":"Javeria Idris","orcid":null,"position":7,"is_corresponding":false},{"id":822886,"name":"Marco Marchetti","orcid":"0000-0003-0776-0486","position":8,"is_corresponding":false},{"id":284606,"name":"Shicong Xie","orcid":"0000-0002-3283-3248","position":10,"is_corresponding":false},{"id":463565,"name":"Lucy Erin O’Brien","orcid":"0000-0001-7660-2524","position":11,"is_corresponding":false},{"id":585766,"name":"Erin Sanders","orcid":"0000-0003-2312-6346","position":0,"is_corresponding":true}],"reference_count":104,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:11:06.395600Z","pmid":"39803552","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":[]}