{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:29:32Z","timestamp":1787005772929,"version":"build-2736575974"},"reference-count":91,"publisher":"National Academy of Sciences","issue":"16","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Clinical Research Collaboration Grant from the Institute of Biomedical Sciences, Academia Sinica","award":["IBMS-CRC108-P01 IBMS-CRC111-P01"],"award-info":[{"award-number":["IBMS-CRC108-P01 IBMS-CRC111-P01"]}]},{"name":"Career Development Award, Academia Sinica","award":["AS-CDA-112-L04"],"award-info":[{"award-number":["AS-CDA-112-L04"]}]},{"name":"Grand Challenge Project, Academia Sinica","award":["AS-GC-110-05"],"award-info":[{"award-number":["AS-GC-110-05"]}]},{"name":"Research Project Grant from the National Science and Technology Council in Taiwan","award":["MOST 108-2320-B-001-032-MY2"],"award-info":[{"award-number":["MOST 108-2320-B-001-032-MY2"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,4,21]]},"abstract":"<jats:p>\n                    Myocardial infarction results in irreversible cardiomyocyte loss and fibrotic remodeling in adult mammals, whereas some vertebrates retain the ability to regenerate cardiac tissue. Comparative studies suggest that immune responses critically influence repair outcomes, yet the immune programs associated with regeneration remain incompletely defined. Here, we investigate how immune modulation accelerates cardiac repair in the nonregenerative medaka (\n                    <jats:italic toggle=\"yes\">Oryzias latipes<\/jats:italic>\n                    ). Using bulk and single-cell transcriptomics combined with functional assays, we show that stimulation with the Toll-like receptor 3 agonist poly I:C accelerates early immune activation and enhances macrophage-dependent debris clearance, associated with inflammatory resolution after cardiac injury. Single-cell analysis of enriched myeloid populations identifies regeneration-associated macrophage subsets characterized by phagocytic and immune-regulatory gene programs, including elevated expression of\n                    <jats:italic toggle=\"yes\">granulin-a<\/jats:italic>\n                    (\n                    <jats:italic toggle=\"yes\">grna<\/jats:italic>\n                    ). Spatial analysis by hybridization chain reaction reveals increased numbers of\n                    <jats:italic toggle=\"yes\">grna<\/jats:italic>\n                    -expressing macrophages in the injury border zone, coinciding with the regenerative niche of cardiomyocyte proliferation. Consistent with these findings, administration of recombinant Granulin A enhances cardiomyocyte proliferation and reduces scar burden in medaka hearts. Together, these findings indicate that immune modulation reshapes macrophage functional states during cardiac repair and link macrophage-associated\n                    <jats:italic toggle=\"yes\">granulin<\/jats:italic>\n                    expression to regenerative outcomes, highlighting macrophage properties as a potential target for improving heart repair.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2524705123","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T18:02:21Z","timestamp":1776189741000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Immune modulation promotes heart regeneration through macrophage and Granulin functions in medaka"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5359-2458","authenticated-orcid":false,"given":"Kaushik","family":"Chowdhury","sequence":"first","affiliation":[{"name":"Institute of Biomedical 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