{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:51:53Z","timestamp":1792788713260,"version":"4.5.0"},"reference-count":67,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:00:00Z","timestamp":1750636800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Global Consortium for Reproductive Longevity & Equality","award":["GCRLE-1223"],"award-info":[{"award-number":["GCRLE-1223"]}]},{"name":"Global Consortium for Reproductive Longevity & Equality","award":["GCRLE-4501"],"award-info":[{"award-number":["GCRLE-4501"]}]},{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01HD105752"],"award-info":[{"award-number":["R01HD105752"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["AG069742"],"award-info":[{"award-number":["AG069742"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["P51 OD011092"],"award-info":[{"award-number":["P51 OD011092"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["U01 AG021382"],"award-info":[{"award-number":["U01 AG021382"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007059","name":"Northwestern University","doi-asserted-by":"publisher","award":["Startup funds"],"award-info":[{"award-number":["Startup funds"]}],"id":[{"id":"10.13039\/100007059","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosbiology.org"],"crossmark-restriction":false},"short-container-title":["PLoS Biol"],"abstract":"<jats:p>\n                    The ovary is one of the first organs to exhibit signs of aging, characterized by reduced tissue function, chronic inflammation, and fibrosis. Multinucleated giant cells (MNGCs), formed by macrophage fusion, typically occur in chronic immune pathologies, including infectious and non-infectious granulomas and the foreign body response, but are also observed in the aging ovary. The function and consequence of ovarian MNGCs remain unknown as their biological activity is highly context-dependent, and their large size has limited their isolation and analysis through technologies such as single-cell RNA sequencing. In this study, we define ovarian MNGCs through a deep analysis of their presence across age and species using advanced imaging technologies as well as their unique transcriptome using laser capture microdissection. MNGCs form complex interconnected networks that increase with age in both mouse and nonhuman primate ovaries. MNGCs are characterized by high\n                    <jats:italic>Gpnmb<\/jats:italic>\n                    expression, a putative marker of ovarian and non-ovarian MNGCs. Pathway analysis highlighted functions in apoptotic cell clearance, lipid metabolism, proteolysis, immune processes, and increased oxidative phosphorylation and antioxidant activity. Thus, MNGCs have signatures related to degradative processes, immune function, and high metabolic activity. These processes were enriched in MNGCs compared to primary ovarian macrophages, suggesting discrete functionality. MNGCs express CD4 and colocalize with T-cells, which were enriched in regions of MNGCs, indicative of a close interaction between these immune cell types. These findings implicate MNGCs in modulation of the ovarian immune landscape during aging given their high penetrance and unique molecular signature that supports degradative and immune functions.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3003204","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T16:01:39Z","timestamp":1750694499000},"page":"e3003204","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":37,"title":["Multinucleated giant cells are hallmarks of ovarian aging with unique immune and degradation-associated molecular signatures"],"prefix":"10.1371","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4203-1687","authenticated-orcid":true,"given":"Aubrey","family":"Converse","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline J.","family":"Perry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shweta S.","family":"Dipali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose V. V.","family":"Isola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmett B.","family":"Kelly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph M.","family":"Varberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary B.","family":"Zelinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael B.","family":"Stout","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele T.","family":"Pritchard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca E.","family":"Duncan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,6,23]]},"reference":[{"issue":"5","key":"pbio.3003204.ref001","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1210\/er.2009-0006","article-title":"Ovarian aging: mechanisms and clinical consequences","volume":"30","author":"FJ Broekmans","year":"2009","journal-title":"Endocr Rev"},{"key":"pbio.3003204.ref002","first-page":"109","article-title":"Female reproductive aging: From consequences to mechanisms, markers, and treatments","volume-title":"Conn\u2019s Handbook of Models for Human Aging","author":"FE Duncan","year":"2018"},{"issue":"3","key":"pbio.3003204.ref003","doi-asserted-by":"crossref","DOI":"10.1530\/REP-19-0501","article-title":"The ovarian stroma as a new frontier","volume":"160","author":"HM Kinnear","year":"2020","journal-title":"Reproduction"},{"key":"pbio.3003204.ref004","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1530\/REP-19-0330","article-title":"Inflammaging is associated with shifted macrophage ontogeny and polarization in the aging mouse ovary","volume":"159","author":"Z Zhang","year":"2020","journal-title":"Reproduction"},{"issue":"9","key":"pbio.3003204.ref005","doi-asserted-by":"crossref","first-page":"4902","DOI":"10.3390\/ijms22094902","article-title":"Fibroinflammatory Signatures Increase with Age in the Human Ovary and Follicular Fluid","volume":"22","author":"JH Machlin","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"3","key":"pbio.3003204.ref006","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1530\/REP-16-0129","article-title":"Reproductive age-associated fibrosis in the stroma of the mammalian ovary","volume":"152","author":"SM Briley","year":"2016","journal-title":"Reproduction"},{"issue":"11","key":"pbio.3003204.ref007","doi-asserted-by":"crossref","DOI":"10.1111\/acel.13259","article-title":"Ovarian stiffness increases with age in the mammalian ovary and depends on collagen and hyaluronan matrices","volume":"19","author":"F Amargant","year":"2020","journal-title":"Aging Cell"},{"key":"pbio.3003204.ref008","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.74915","article-title":"Single-cell analysis of the aged ovarian immune system reveals a shift towards adaptive immunity and attenuated cell function","volume":"12","author":"T Ben Yaakov","year":"2023","journal-title":"Elife"},{"issue":"35","key":"pbio.3003204.ref009","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.abq1475","article-title":"Metformin prevents age-associated ovarian fibrosis by modulating the immune landscape in female mice","volume":"8","author":"DA Landry","year":"2022","journal-title":"Sci Adv"},{"issue":"20","key":"pbio.3003204.ref010","first-page":"10821","article-title":"Proteomic quantification of native and ECM-enriched mouse ovaries reveals an age-dependent fibro-inflammatory signature","volume":"15","author":"SS Dipali","year":"2023","journal-title":"Aging (Albany NY)"},{"key":"pbio.3003204.ref011","article-title":"Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases","author":"C Franceschi","year":"2014","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"24","key":"pbio.3003204.ref012","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.abn4564","article-title":"Female reproductive life span is extended by targeted removal of fibrotic collagen from the mouse ovary","volume":"8","author":"T Umehara","year":"2022","journal-title":"Sci Adv"},{"key":"pbio.3003204.ref013","article-title":"Systemic low-dose anti-fibrotic treatment attenuates ovarian aging in the mouse","author":"F Amargant","year":"2024","journal-title":"BioRxiv"},{"issue":"6","key":"pbio.3003204.ref014","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.ajpath.2019.02.006","article-title":"An Overview of the Derivation and Function of Multinucleated Giant Cells and Their Role in Pathologic Processes","volume":"189","author":"PJ Brooks","year":"2019","journal-title":"Am J Pathol"},{"key":"pbio.3003204.ref015","doi-asserted-by":"crossref","first-page":"873226","DOI":"10.3389\/fcell.2022.873226","article-title":"Multinucleated Giant Cells: Current Insights in Phenotype, Biological Activities, and Mechanism of Formation","volume":"10","author":"K Ahmadzadeh","year":"2022","journal-title":"Front Cell Dev Biol"},{"issue":"3","key":"pbio.3003204.ref016","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1369\/0022155411431734","article-title":"Age-related accumulation of non-heme ferric and ferrous iron in mouse ovarian stroma visualized by sensitive non-heme iron histochemistry","volume":"60","author":"Y Asano","year":"2012","journal-title":"J Histochem Cytochem"},{"issue":"2","key":"pbio.3003204.ref017","doi-asserted-by":"crossref","DOI":"10.1530\/REP-20-0489","article-title":"Macrophage-derived multinucleated giant cells: hallmarks of the aging ovary","volume":"161","author":"KG Foley","year":"2021","journal-title":"Reproduction"},{"issue":"1","key":"pbio.3003204.ref018","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/s43587-023-00552-5","article-title":"A single-cell atlas of the aging mouse ovary","volume":"4","author":"JVV Isola","year":"2024","journal-title":"Nat Aging"},{"key":"pbio.3003204.ref019","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/978-1-4939-6670-7_10","volume-title":"The Specifi c Histochemical Stain for Lipofuscin: A Novel Method to Detect Senescent Cells. Oncogene-Induced Senescence Methods and Protocols","author":"K Evangelou","year":"2017"},{"key":"pbio.3003204.ref020","doi-asserted-by":"crossref","first-page":"111425","DOI":"10.1016\/j.mad.2020.111425","article-title":"Cellular hallmarks of aging emerge in the ovary prior to primordial follicle depletion","volume":"194","author":"VA Ansere","year":"2021","journal-title":"Mech Ageing Dev"},{"key":"pbio.3003204.ref021","first-page":"1289103","article-title":"Parity-Dependent Hemosiderin and Lipofuscin Accumulation in the Reproductively Aged Mouse Ovary","volume":"2018","author":"U Urzua","year":"2018","journal-title":"Anal Cell Pathol (Amst)"},{"issue":"1","key":"pbio.3003204.ref022","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/s41514-024-00157-1","article-title":"The role of cellular senescence in ovarian aging","volume":"10","author":"JD Hense","year":"2024","journal-title":"NPJ Aging"},{"key":"pbio.3003204.ref023","doi-asserted-by":"crossref","first-page":"621","DOI":"10.2147\/JIR.S337241","article-title":"Insight into the Molecular Characteristics of Langhans Giant Cell by Combination of Laser Capture Microdissection and RNA Sequencing","volume":"15","author":"Y Chen","year":"2022","journal-title":"J Inflamm Res"},{"issue":"3","key":"pbio.3003204.ref024","doi-asserted-by":"crossref","DOI":"10.15252\/embr.202256310","article-title":"Multinucleation resets human macrophages for specialized functions at the expense of their identity","volume":"24","author":"K Ahmadzadeh","year":"2023","journal-title":"EMBO Rep"},{"issue":"3","key":"pbio.3003204.ref025","doi-asserted-by":"crossref","first-page":"151952","DOI":"10.1016\/j.imbio.2020.151952","article-title":"Multinucleated giant cell phenotype in response to stimulation","volume":"225","author":"KL Trout","year":"2020","journal-title":"Immunobiology"},{"issue":"8","key":"pbio.3003204.ref026","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1161\/CIRCRESAHA.121.320449","article-title":"Transcriptional and Immune Landscape of Cardiac Sarcoidosis","volume":"131","author":"J Liu","year":"2022","journal-title":"Circ Res"},{"issue":"12","key":"pbio.3003204.ref027","article-title":"Different Molecular Features of Epithelioid and Giant Cells in Foreign Body Reaction Identified by Single-Cell RNA Sequencing","volume":"142","author":"Y-S Kim","year":"2022","journal-title":"J Invest Dermatol"},{"key":"pbio.3003204.ref028","article-title":"Transcriptomic signatures of mouse ovarian aging and estropausal transition at single cell resolution","author":"X Wang","year":"2024","journal-title":"bioRxiv"},{"issue":"10","key":"pbio.3003204.ref029","doi-asserted-by":"crossref","first-page":"6557","DOI":"10.4049\/jimmunol.178.10.6557","article-title":"Gpnmb is induced in macrophages by IFN-gamma and lipopolysaccharide and acts as a feedback regulator of proinflammatory responses","volume":"178","author":"VM Ripoll","year":"2007","journal-title":"J Immunol"},{"key":"pbio.3003204.ref030","doi-asserted-by":"crossref","first-page":"674739","DOI":"10.3389\/fimmu.2021.674739","article-title":"The Role of GPNMB in Inflammation","volume":"12","author":"M Saade","year":"2021","journal-title":"Front Immunol"},{"issue":"11","key":"pbio.3003204.ref031","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0143413","article-title":"Glycoprotein Nonmetastatic Melanoma B (Gpnmb)-Positive Macrophages Contribute to the Balance between Fibrosis and Fibrolysis during the Repair of Acute Liver Injury in Mice","volume":"10","author":"K Kumagai","year":"2015","journal-title":"PLoS One"},{"issue":"1","key":"pbio.3003204.ref032","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/s42003-022-04333-5","article-title":"Macrophage-derived GPNMB trapped by fibrotic extracellular matrix promotes pulmonary fibrosis","volume":"6","author":"J Wang","year":"2023","journal-title":"Commun Biol"},{"key":"pbio.3003204.ref033","doi-asserted-by":"crossref","first-page":"248","DOI":"10.2152\/jmi.54.248","article-title":"Overexpression of osteoactivin protects skeletal muscle from severe degeneration caused by long-term denervation in mice","volume":"54","author":"H Furochi","year":"2007","journal-title":"J Med Invest"},{"issue":"12","key":"pbio.3003204.ref034","first-page":"4767","article-title":"The melanoma-associated transmembrane glycoprotein Gpnmb controls trafficking of cellular debris for degradation and is essential for tissue repair","volume":"24","author":"B Li","year":"2010","journal-title":"FASEB J"},{"key":"pbio.3003204.ref035","doi-asserted-by":"crossref","first-page":"9636897241233040","DOI":"10.1177\/09636897241233040","article-title":"GPNMB Modulates Autophagy to Enhance Functional Recovery After Spinal Cord Injury in Rats","volume":"33","author":"X Li","year":"2024","journal-title":"Cell Transplant"},{"issue":"1","key":"pbio.3003204.ref036","doi-asserted-by":"crossref","first-page":"6522","DOI":"10.1038\/s41598-022-10522-3","article-title":"Glycoprotein nonmetastatic melanoma protein B regulates lysosomal integrity and lifespan of senescent cells","volume":"12","author":"M Suda","year":"2022","journal-title":"Sci Rep"},{"issue":"1","key":"pbio.3003204.ref037","doi-asserted-by":"crossref","first-page":"10249","DOI":"10.1038\/s41598-021-89800-5","article-title":"Quantitative trait locus mapping identifies the Gpnmb gene as a modifier of mouse macrophage lysosome function","volume":"11","author":"P Robinet","year":"2021","journal-title":"Sci Rep"},{"issue":"1","key":"pbio.3003204.ref038","doi-asserted-by":"crossref","first-page":"12171","DOI":"10.1038\/s41598-021-91588-3","article-title":"Expression pattern and prognostic impact of glycoprotein non-metastatic B (GPNMB) in triple-negative breast cancer","volume":"11","author":"Y-H Huang","year":"2021","journal-title":"Sci Rep"},{"issue":"1","key":"pbio.3003204.ref039","doi-asserted-by":"crossref","first-page":"36","DOI":"10.3892\/ol.2021.13154","article-title":"GPNMB overexpression is associated with extensive bone metastasis and poor prognosis in renal cell carcinoma","volume":"23","author":"J-P Zhai","year":"2022","journal-title":"Oncol Lett"},{"issue":"10","key":"pbio.3003204.ref040","doi-asserted-by":"crossref","first-page":"2960","DOI":"10.7150\/jca.92661","article-title":"GPNMB Expression Associates with Inferior Prognosis in Patients with Small Cell Lung Cancer","volume":"15","author":"Q Liu","year":"2024","journal-title":"J Cancer"},{"issue":"8","key":"pbio.3003204.ref041","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1530\/EC-20-0240","article-title":"Elevated circulating Gpnmb levels are associated with hyperthyroidism","volume":"9","author":"J Lin","year":"2020","journal-title":"Endocr Connect"},{"issue":"41","key":"pbio.3003204.ref042","doi-asserted-by":"crossref","first-page":"4573","DOI":"10.1038\/s41388-022-02443-2","article-title":"GPNMB: a potent inducer of immunosuppression in cancer","volume":"41","author":"A-M Lazaratos","year":"2022","journal-title":"Oncogene"},{"issue":"7","key":"pbio.3003204.ref043","doi-asserted-by":"crossref","first-page":"8810","DOI":"10.1096\/fj.202000651","article-title":"Glycoprotein nonmetastatic melanoma protein B: A key mediator and an emerging therapeutic target in autoimmune diseases","volume":"34","author":"P-S Tsou","year":"2020","journal-title":"FASEB J"},{"issue":"12","key":"pbio.3003204.ref044","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1038\/s43587-021-00151-2","article-title":"Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice","volume":"1","author":"M Suda","year":"2021","journal-title":"Nat Aging"},{"issue":"10","key":"pbio.3003204.ref045","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1016\/j.febslet.2008.03.030","article-title":"Osteoactivin is a novel osteoclastic protein and plays a key role in osteoclast differentiation and activity","volume":"582","author":"MH-C Sheng","year":"2008","journal-title":"FEBS Lett"},{"issue":"1","key":"pbio.3003204.ref046","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1038\/s41467-021-22103-5","article-title":"Monocyte progenitors give rise to multinucleated giant cells","volume":"12","author":"AK L\u00f6sslein","year":"2021","journal-title":"Nat Commun"},{"key":"pbio.3003204.ref047","doi-asserted-by":"crossref","first-page":"101688","DOI":"10.1016\/j.bonr.2023.101688","article-title":"Oxidative phosphorylation in bone cells","volume":"18","author":"E Sabini","year":"2023","journal-title":"Bone Rep"},{"issue":"45","key":"pbio.3003204.ref048","doi-asserted-by":"crossref","first-page":"37808","DOI":"10.1074\/jbc.M112.385369","article-title":"Intracellular and extracellular ATP coordinately regulate the inverse correlation between osteoclast survival and bone resorption","volume":"287","author":"T Miyazaki","year":"2012","journal-title":"J Biol Chem"},{"key":"pbio.3003204.ref049","doi-asserted-by":"crossref","first-page":"816005","DOI":"10.3389\/fimmu.2022.816005","article-title":"CD3+CD4-CD8- (Double-Negative) T Cells in Inflammation, Immune Disorders and Cancer","volume":"13","author":"Z Wu","year":"2022","journal-title":"Front Immunol"},{"key":"pbio.3003204.ref050","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.cellimm.2013.06.011","article-title":"Helper T cells down-regulate CD4 expression upon chronic stimulation giving rise to double-negative T cells","volume":"284","author":"IV Grishkan","year":"2013","journal-title":"Cell Immunol"},{"issue":"3","key":"pbio.3003204.ref051","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1002\/JLB.1AB0120-548R","article-title":"TCR-\u03b1\/\u03b2 CD4- CD8- double negative T cells arise from CD8+ T cells","volume":"108","author":"N Rodr\u00edguez-Rodr\u00edguez","year":"2020","journal-title":"J Leukoc Biol"},{"issue":"4","key":"pbio.3003204.ref052","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.bcp.2011.05.019","article-title":"CD3+CD4-CD8- (double negative) T cells: saviours or villains of the immune response?","volume":"82","author":"F D\u2019Acquisto","year":"2011","journal-title":"Biochem Pharmacol"},{"issue":"1","key":"pbio.3003204.ref053","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"S Jin","year":"2021","journal-title":"Nat Commun"},{"issue":"9","key":"pbio.3003204.ref054","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1016\/j.jid.2020.01.026","article-title":"Cellular, Molecular, and Immunological Characteristics of Langhans Multinucleated Giant Cells Programmed by IL-15","volume":"140","author":"H Wang","year":"2020","journal-title":"J Invest Dermatol"},{"key":"pbio.3003204.ref055","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.imlet.2003.11.023","article-title":"T cell contributions to the different phases of granuloma formation","volume":"92","author":"DO Co","year":"2004","journal-title":"Immunol Lett"},{"key":"pbio.3003204.ref056","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0008-8749(02)00510-5","article-title":"CD4 is required for the development of a protective granulomatous response to pulmonary tuberculosis","volume":"216","author":"BM Saunders","year":"2002","journal-title":"Cell Immunol"},{"issue":"1","key":"pbio.3003204.ref057","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1002\/jbm.a.32050","article-title":"The foreign body reaction in T-cell-deficient mice","volume":"90","author":"A Rodriguez","year":"2009","journal-title":"J Biomed Mater Res A"},{"issue":"4","key":"pbio.3003204.ref058","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1002\/jcp.22411","article-title":"T cell suppression by osteoclasts in vitro","volume":"226","author":"F Grassi","year":"2011","journal-title":"J Cell Physiol"},{"issue":"9","key":"pbio.3003204.ref059","doi-asserted-by":"crossref","first-page":"5477","DOI":"10.4049\/jimmunol.0803897","article-title":"Cross-presentation by osteoclasts induces FoxP3 in CD8+ T cells","volume":"182","author":"JR Kiesel","year":"2009","journal-title":"J Immunol"},{"issue":"2","key":"pbio.3003204.ref060","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1182\/blood-2009-11-255026","article-title":"Cross talk between the bone and immune systems: osteoclasts function as antigen-presenting cells and activate CD4+ and CD8+ T cells","volume":"116","author":"H Li","year":"2010","journal-title":"Blood"},{"issue":"1","key":"pbio.3003204.ref061","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/s41592-023-02098-1","article-title":"The Cousa objective: a long-working distance air objective for multiphoton imaging in vivo","volume":"21","author":"C-H Yu","year":"2024","journal-title":"Nat Methods"},{"key":"pbio.3003204.ref062","doi-asserted-by":"crossref","first-page":"10","DOI":"10.14806\/ej.17.1.200","article-title":"Cutadapt removes adapter sequences from hgh-throughput sequencing reads","volume":"17","author":"M Martin","year":"2011","journal-title":"EMBnet J"},{"issue":"1","key":"pbio.3003204.ref063","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"A Dobin","year":"2013","journal-title":"Bioinformatics"},{"issue":"2","key":"pbio.3003204.ref064","first-page":"166","article-title":"HTSeq\u2014a Python framework to work with high-throughput sequencing data","volume":"31","year":"2014","journal-title":"Bioinformatics"},{"issue":"12","key":"pbio.3003204.ref065","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"MI Love","year":"2014","journal-title":"Genome Biol"},{"issue":"1","key":"pbio.3003204.ref066","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Y Zhou","year":"2019","journal-title":"Nat Commun"},{"key":"pbio.3003204.ref067","article-title":"Multinucleated giant cells are hallmarks of ovarian aging with unique immune and degradation-associated molecular signatures","author":"A Converse","year":"2025","journal-title":"Dryad Digital Repository"}],"container-title":["PLOS Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3003204","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T16:01:53Z","timestamp":1750694513000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3003204"}},"subtitle":[],"editor":[{"given":"Masahito","family":"Ikawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,6,23]]},"references-count":67,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6,23]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pbio.3003204","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.12.03.626649","asserted-by":"object"}]},"ISSN":["1545-7885"],"issn-type":[{"value":"1545-7885","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,23]]}}}