{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T22:40:29Z","timestamp":1759963229416,"version":"build-2065373602"},"reference-count":53,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T00:00:00Z","timestamp":1753056000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["ZIADE000746","ZICDC000086"],"award-info":[{"award-number":["ZIADE000746","ZICDC000086"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Large\u2010scale bone defects require complex surgical procedures to repair, but full restoration of the bone is not guaranteed due to the significant tissue loss involved. In contrast, fractures can frequently be treated with conservative techniques. Particularly, ribs have a remarkable ability to spontaneously regenerate large\u2010scale bone defects. However, we show here that skeletal maturity and age are associated with a decrease in the regenerative potential of human ribs. To investigate skeletal maturity and age\u2010related cellular and transcriptional changes during large\u2010scale bone regeneration, we used a mouse model that mimics the regenerative clinical features of human ribs. Unlike immature mice, mature mice lose the ability to regenerate after rib resection, and instead of bone, the resected rib space is repaired with abundant fibronectin cells. In addition, bone repair in mature mice presents reduced immune cell infiltration, which coincides with decreased levels of circulatory pro\u2010inflammatory factors. To address the role of cell\u2013cell communication and test whether skeletal maturity and age\u2010related changes in immune cells and circulatory factors influence bone regeneration, we used immunodeficient mouse strains and performed heterochronic parabiosis. In immature mice, defective immune cell function altered callus composition rather than inhibiting bone regeneration. Remarkably, under parabiosis, a systemic pro\u2010regenerative response is triggered exclusively in resected immature mice and is capable of partially rescuing bone regeneration in mature mice otherwise unable to regenerate spontaneously. Collectively, these findings suggest that therapeutic strategies focused on identifying pro\u2010regenerative immune factors are promising for supporting the regeneration of large bone defects.<\/jats:p>","DOI":"10.1111\/acel.70177","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T07:35:15Z","timestamp":1753083315000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Skeletal Maturity and Age\u2010Related Changes in Immune Cells and Circulatory Factors Impair Large\u2010Scale Bone Regeneration"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5403-4052","authenticated-orcid":false,"given":"Luciana Yamamoto","family":"de Almeida","sequence":"first","affiliation":[{"name":"Craniofacial Anomalies and Regeneration Section National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catharine","family":"Dietrich","sequence":"additional","affiliation":[{"name":"Craniofacial Anomalies and Regeneration Section National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashleigh S.","family":"Hanner","sequence":"additional","affiliation":[{"name":"Craniofacial Anomalies and Regeneration Section National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katelyn M.","family":"McTighe","sequence":"additional","affiliation":[{"name":"Craniofacial Anomalies and Regeneration Section National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8880-9087","authenticated-orcid":false,"given":"Daniel","family":"Martin","sequence":"additional","affiliation":[{"name":"Genomics and Computational Biology Core National Institute on Deafness and Other Communication Disorders (NIDCD)\/NIDCR  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"NIDCD\/NIDCR Genomics and Computational Biology Core","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Todd","family":"Fairbanks","sequence":"additional","affiliation":[{"name":"Department of Oral &amp; Maxillofacial Surgery University of California San Francisco  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas M.","family":"Link","sequence":"additional","affiliation":[{"name":"Department of Oral &amp; Maxillofacial Surgery University of California San Francisco  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John M.","family":"Le","sequence":"additional","affiliation":[{"name":"Craniofacial Anomalies and Regeneration Section National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natasha","family":"Curry","sequence":"additional","affiliation":[{"name":"Craniofacial Anomalies and Regeneration Section National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Priyam","family":"Jani","sequence":"additional","affiliation":[{"name":"Craniofacial Anomalies and Regeneration Section National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Gao","sequence":"additional","affiliation":[{"name":"Craniofacial Anomalies and Regeneration Section National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenli","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Oral &amp; Maxillofacial Surgery University of California San Francisco  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca V.","family":"Mariani","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine University of Southern California  Los Angeles California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivier","family":"Duverger","sequence":"additional","affiliation":[{"name":"Craniofacial Anomalies and Regeneration Section National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janice S.","family":"Lee","sequence":"additional","affiliation":[{"name":"Craniofacial Anomalies and Regeneration Section National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_2_11_2_1","DOI":"10.1093\/bioinformatics\/btab003"},{"doi-asserted-by":"publisher","key":"e_1_2_11_3_1","DOI":"10.1038\/s41586\u2010021\u201003795\u20107"},{"doi-asserted-by":"publisher","key":"e_1_2_11_4_1","DOI":"10.1016\/j.stem.2017.02.009"},{"doi-asserted-by":"publisher","key":"e_1_2_11_5_1","DOI":"10.1038\/ncomms8131"},{"doi-asserted-by":"publisher","key":"e_1_2_11_6_1","DOI":"10.3389\/fimmu.2018.01804"},{"doi-asserted-by":"publisher","key":"e_1_2_11_7_1","DOI":"10.1186\/ar1833"},{"doi-asserted-by":"publisher","key":"e_1_2_11_8_1","DOI":"10.1016\/j.cell.2014.12.002"},{"doi-asserted-by":"publisher","key":"e_1_2_11_9_1","DOI":"10.4049\/jimmunol.181.2.1232"},{"doi-asserted-by":"publisher","key":"e_1_2_11_10_1","DOI":"10.1073\/pnas.2017889118"},{"doi-asserted-by":"publisher","key":"e_1_2_11_11_1","DOI":"10.1111\/acel.13112"},{"doi-asserted-by":"publisher","key":"e_1_2_11_12_1","DOI":"10.1007\/s11914\u2010017\u20100413\u20109"},{"doi-asserted-by":"publisher","key":"e_1_2_11_13_1","DOI":"10.1359\/jbmr.081003"},{"doi-asserted-by":"publisher","key":"e_1_2_11_14_1","DOI":"10.1038\/srep38616"},{"doi-asserted-by":"publisher","key":"e_1_2_11_15_1","DOI":"10.1007\/s004020050263"},{"doi-asserted-by":"publisher","key":"e_1_2_11_16_1","DOI":"10.1038\/s41467\u2010018\u201003124\u2010z"},{"doi-asserted-by":"publisher","key":"e_1_2_11_17_1","DOI":"10.3390\/ijms19082239"},{"doi-asserted-by":"publisher","key":"e_1_2_11_18_1","DOI":"10.3389\/fimmu.2017.00562"},{"doi-asserted-by":"publisher","key":"e_1_2_11_19_1","DOI":"10.3324\/haematol.2018.211342"},{"doi-asserted-by":"publisher","key":"e_1_2_11_20_1","DOI":"10.1016\/j.maturitas.2016.07.014"},{"doi-asserted-by":"publisher","key":"e_1_2_11_21_1","DOI":"10.1002\/dvdy.278"},{"doi-asserted-by":"publisher","key":"e_1_2_11_22_1","DOI":"10.1172\/JCI98857"},{"doi-asserted-by":"publisher","key":"e_1_2_11_23_1","DOI":"10.1002\/jor.23652"},{"doi-asserted-by":"publisher","key":"e_1_2_11_24_1","DOI":"10.1073\/pnas.1810692116"},{"doi-asserted-by":"publisher","key":"e_1_2_11_25_1","DOI":"10.3791\/50556"},{"doi-asserted-by":"publisher","key":"e_1_2_11_26_1","DOI":"10.7554\/eLife.40715"},{"doi-asserted-by":"publisher","key":"e_1_2_11_27_1","DOI":"10.1016\/j.ydbio.2015.01.022"},{"doi-asserted-by":"publisher","key":"e_1_2_11_28_1","DOI":"10.3389\/fimmu.2019.02443"},{"doi-asserted-by":"publisher","key":"e_1_2_11_29_1","DOI":"10.1016\/j.bone.2016.02.020"},{"doi-asserted-by":"publisher","key":"e_1_2_11_30_1","DOI":"10.3389\/fphys.2023.1087254"},{"doi-asserted-by":"publisher","key":"e_1_2_11_31_1","DOI":"10.7554\/eLife.58534"},{"doi-asserted-by":"publisher","key":"e_1_2_11_32_1","DOI":"10.1097\/00000637\u2010198111000\u201000001"},{"doi-asserted-by":"publisher","key":"e_1_2_11_33_1","DOI":"10.1038\/s41591\u2010020\u20101013\u20102"},{"doi-asserted-by":"publisher","key":"e_1_2_11_34_1","DOI":"10.1016\/j.ajpath.2017.10.011"},{"doi-asserted-by":"publisher","key":"e_1_2_11_35_1","DOI":"10.1016\/j.ajpath.2014.08.017"},{"doi-asserted-by":"publisher","key":"e_1_2_11_36_1","DOI":"10.1371\/journal.pone.0147465"},{"doi-asserted-by":"publisher","key":"e_1_2_11_37_1","DOI":"10.1016\/j.bone.2014.08.007"},{"doi-asserted-by":"publisher","key":"e_1_2_11_38_1","DOI":"10.1097\/00006534\u2010199704001\u201000005"},{"doi-asserted-by":"publisher","key":"e_1_2_11_39_1","DOI":"10.1097\/bot.0000000000000978"},{"doi-asserted-by":"publisher","key":"e_1_2_11_40_1","DOI":"10.1016\/j.bone.2015.10.019"},{"doi-asserted-by":"publisher","key":"e_1_2_11_41_1","DOI":"10.1038\/s41536\u2010022\u201000225\u20108"},{"doi-asserted-by":"publisher","key":"e_1_2_11_42_1","DOI":"10.3390\/ijms19123928"},{"doi-asserted-by":"publisher","key":"e_1_2_11_43_1","DOI":"10.1002\/jbmr.185"},{"doi-asserted-by":"publisher","key":"e_1_2_11_44_1","DOI":"10.7554\/eLife.71542"},{"doi-asserted-by":"publisher","key":"e_1_2_11_45_1","DOI":"10.3791\/52375"},{"doi-asserted-by":"publisher","key":"e_1_2_11_46_1","DOI":"10.1016\/j.joca.2016.02.008"},{"doi-asserted-by":"publisher","key":"e_1_2_11_47_1","DOI":"10.1038\/s41586\u2010020\u20102050\u20101"},{"doi-asserted-by":"publisher","key":"e_1_2_11_48_1","DOI":"10.1038\/s41467\u2010018\u201007666\u20100"},{"doi-asserted-by":"publisher","key":"e_1_2_11_49_1","DOI":"10.4252\/wjsc.v11.i6.281"},{"doi-asserted-by":"publisher","key":"e_1_2_11_50_1","DOI":"10.3892\/br.2020.1360"},{"doi-asserted-by":"publisher","key":"e_1_2_11_51_1","DOI":"10.1242\/bio.021436"},{"doi-asserted-by":"publisher","key":"e_1_2_11_52_1","DOI":"10.1038\/s41598\u2010024\u201076992\u20109"},{"doi-asserted-by":"publisher","key":"e_1_2_11_53_1","DOI":"10.3389\/fendo.2021.666140"},{"doi-asserted-by":"publisher","key":"e_1_2_11_54_1","DOI":"10.1111\/acel.13651"}],"container-title":["Aging Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70177","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T22:05:53Z","timestamp":1759961153000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/acel.70177"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,21]]},"references-count":53,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1111\/acel.70177"],"URL":"https:\/\/doi.org\/10.1111\/acel.70177","archive":["Portico"],"relation":{},"ISSN":["1474-9718","1474-9726"],"issn-type":[{"type":"print","value":"1474-9718"},{"type":"electronic","value":"1474-9726"}],"subject":[],"published":{"date-parts":[[2025,7,21]]},"assertion":[{"value":"2025-01-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70177"}}