{"doi":"10.1101/2023.07.12.548764","title":"Oncostatin M is a Master Regulator of an Inflammatory Network in <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells","abstract":"ABSTRACT Age-associated clonal hematopoiesis (CH) occurs due to somatic mutations accrued in hematopoietic stem cells (HSCs) that confer a selective advantage in the context of aging. The mechanisms by which CH-mutant HSCs gain this advantage with aging are not comprehensively understood. Using unbiased transcriptomic approaches, we identify Oncostatin M (OSM) signaling as a candidate contributor to aging-driven Dnmt3a -mutant CH. We find that Dnmt3a -mutant HSCs from young mice do not functionally respond to acute OSM stimulation with respect to proliferation, apoptosis, hematopoietic engraftment, or myeloid differentiation. However, young Dnmt3a -mutant HSCs transcriptionally upregulate an inflammatory cytokine network in response to acute OSM stimulation including genes encoding IL-6, IL-1β and TNFα. In addition, OSM-stimulated Dnmt3a -mutant HSCs upregulate the anti-inflammatory genes Socs3, Atf3 and Nr4a1 , creating a negative feedback loop limiting sustained activation of the inflammatory network. In the context of an aged bone marrow (BM) microenvironment with chronically elevated levels of OSM, Dnmt3a -mutant HSCs upregulate pro-inflammatory genes but do not upregulate Socs3, Atf3 and Nr4a1 . Together, our work suggests that chronic inflammation with aging exhausts the regulatory mechanisms in young CH-mutant HSCs that resolve inflammatory states, and that OSM is a master regulator of an inflammatory network that contributes to age-associated CH.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":400101,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9589,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":320294,"name":"Kira Young","orcid":"0000-0002-1598-9793","position":1,"is_corresponding":false},{"id":572381,"name":"Timothy M. Stearns","orcid":"0000-0002-5533-6076","position":2,"is_corresponding":false},{"id":876003,"name":"Nathan Boyer","orcid":"0000-0003-3908-0856","position":3,"is_corresponding":false},{"id":534701,"name":"Kristina D. Mujica","orcid":"0000-0003-4129-0465","position":4,"is_corresponding":false},{"id":302104,"name":"Jennifer J. Trowbridge","orcid":"0000-0002-7636-9504","position":5,"is_corresponding":false},{"id":534700,"name":"Logan S. Schwartz","orcid":"0000-0001-6724-0787","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T01:20:00.023537Z","pmid":"37502912","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":[]}