{"doi":"10.1084/jem.20210420","title":"A growth factor–expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15","abstract":"Muscle regeneration is the result of the concerted action of multiple cell types driven by the temporarily controlled phenotype switches of infiltrating monocyte-derived macrophages. Pro-inflammatory macrophages transition into a phenotype that drives tissue repair through the production of effectors such as growth factors. This orchestrated sequence of regenerative inflammatory events, which we termed regeneration-promoting program (RPP), is essential for proper repair. However, it is not well understood how specialized repair-macrophage identity develops in the RPP at the transcriptional level and how induced macrophage-derived factors coordinate tissue repair. Gene expression kinetics-based clustering of blood circulating Ly6Chigh, infiltrating inflammatory Ly6Chigh, and reparative Ly6Clow macrophages, isolated from injured muscle, identified the TGF-β superfamily member, GDF-15, as a component of the RPP. Myeloid GDF-15 is required for proper muscle regeneration following acute sterile injury, as revealed by gain- and loss-of-function studies. Mechanistically, GDF-15 acts both on proliferating myoblasts and on muscle-infiltrating myeloid cells. Epigenomic analyses of upstream regulators of Gdf15 expression identified that it is under the control of nuclear receptors RXR/PPARγ. Finally, immune single-cell RNA-seq profiling revealed that Gdf15 is coexpressed with other known muscle regeneration-associated growth factors, and their expression is limited to a unique subpopulation of repair-type macrophages (growth factor-expressing macrophages [GFEMs]).","journal":"The Journal of Experimental Medicine","year":2021,"id":150633,"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":91,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9434,"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":514947,"name":"László Halász","orcid":"0000-0003-4726-7012","position":1,"is_corresponding":false},{"id":640427,"name":"Miguel A. Medina-Serpas","orcid":"0000-0003-0532-5413","position":2,"is_corresponding":false},{"id":550893,"name":"Wilhelm K. Berger","orcid":"0000-0003-0727-7064","position":3,"is_corresponding":false},{"id":237496,"name":"Bence Dániel","orcid":"0000-0002-2410-8767","position":4,"is_corresponding":false},{"id":550894,"name":"Petros Tzerpos","orcid":"0000-0002-0398-0855","position":5,"is_corresponding":false},{"id":640428,"name":"Máté Kiss","orcid":"0000-0002-5649-0382","position":6,"is_corresponding":false},{"id":483507,"name":"Gergely Nagy","orcid":"0000-0002-3273-731X","position":7,"is_corresponding":false},{"id":98224,"name":"Cornelius Fischer","orcid":"0000-0003-0329-2435","position":8,"is_corresponding":false},{"id":640429,"name":"Zoltán Simándi","orcid":"0000-0001-8894-1259","position":9,"is_corresponding":false},{"id":640430,"name":"Tamás Varga","orcid":"0000-0002-5303-1850","position":10,"is_corresponding":false},{"id":483508,"name":"László Nagy","orcid":"0000-0001-6653-2155","position":11,"is_corresponding":false},{"id":640426,"name":"Andreas Patsalos","orcid":"0000-0002-9022-4985","position":0,"is_corresponding":true}],"reference_count":136,"raw_metadata":null,"created_at":"2026-07-18T23:43:06.501849Z","pmid":"34846534","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":[]}