{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:39:54Z","timestamp":1786977594781,"version":"build-2736575974"},"reference-count":54,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T00:00:00Z","timestamp":1763337600000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81771577"],"award-info":[{"award-number":["81771577"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82401870"],"award-info":[{"award-number":["82401870"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82101819"],"award-info":[{"award-number":["82101819"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2023A1515012310"],"award-info":[{"award-number":["2023A1515012310"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2023A1515012290"],"award-info":[{"award-number":["2023A1515012290"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2024A1515010094"],"award-info":[{"award-number":["2024A1515010094"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2024A1515010492"],"award-info":[{"award-number":["2024A1515010492"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2025A04J4171"],"award-info":[{"award-number":["2025A04J4171"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Testicular macrophages (TMs) are key regulators of testicular immune privilege and endocrine function in the testis. However, their age\u2010related heterogeneity and role in testicular degeneration remain poorly characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed spatial transcriptomics and FACS\u2010enriched single\u2010cell RNA sequencing (scRNA\u2010seq) to characterize testicular macrophage heterogeneity across ageing. Key findings were validated through intratesticular injection of recombinant CCL8 protein, organotypic culture of seminiferous tubules, and immunofluorescence analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Using spatial transcriptomics, we identified pronounced Leydig niche senescence in aged testes, mechanistically linked to TM\u2010mediated inflammatory remodelling. Coupling FACS\u2010enriched TM isolation with scRNA\u2010seq resolved seven transcriptionally distinct subpopulations, including ageing\u2010associated subsets (\n                      <jats:italic>Ccl8<\/jats:italic>\n                      <jats:sup>hi<\/jats:sup>\n                      and\n                      <jats:italic>Cxcl13<\/jats:italic>\n                      <jats:sup>hi<\/jats:sup>\n                      ). These subsets exhibited inflammatory signalling rewiring (e.g., CCL8\u2010CCR2 axis) and activation of senescence transcriptional regulators (\n                      <jats:italic>ASCL2<\/jats:italic>\n                      ,\n                      <jats:italic>SPI1<\/jats:italic>\n                      ,\n                      <jats:italic>CEBPB<\/jats:italic>\n                      ,\n                      <jats:italic>JUNB<\/jats:italic>\n                      ), with conserved mediators (\n                      <jats:italic>CCL8<\/jats:italic>\n                      ,\n                      <jats:italic>TREM2<\/jats:italic>\n                      ,\n                      <jats:italic>IL1\u03b2<\/jats:italic>\n                      , and\n                      <jats:italic>CXCL2<\/jats:italic>\n                      ) across murine and human testes. Functional validation showed that intratesticular injection of recombinant CCL8 protein in 3\u2010month\u2010old mice recapitulated ageing phenotypes, such as germ cell apoptosis and steroidogenic decline.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our multi\u2010omics atlas highlights TM heterogeneity as a driver of testicular inflammaging and identifies\n                      <jats:italic>CCL8<\/jats:italic>\n                      as a conserved target for therapeutic interventions aimed at mitigating age\u2010associated male reproductive decline.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list>\n                        <jats:list-item>\n                          <jats:p>Spatiotemporal multi\u2011omics establish inflammaging as a defining feature of testicular ageing.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>A refined CD74\u2011based sorting strategy improves enrichment of testicular macrophages.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>scRNA\u2010seq resolves seven TM subsets with age\u2011dependent shifts.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>TM\u2011secreted inflammatory mediators\u2010especially CCL8\u2010drive testicular inflammaging.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70527","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T07:02:08Z","timestamp":1763449328000},"source":"Crossref","is-referenced-by-count":7,"title":["Spatiotemporal mapping reveals Ccl8\n                    <sup>hi<\/sup>\n                    macrophages as key drivers of testicular inflammaging"],"prefix":"10.1002","volume":"15","author":[{"given":"Yanping","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Urology and Andrology Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Andrology  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Yao","sequence":"additional","affiliation":[{"name":"Zhongshan School of Medicine Sun Yat\u2010sen University  Guangzhou China"},{"name":"Department of Urology and Andrology The First Affiliated Hospital, Sun Yat\u2010sen University  Guangzhou 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