{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:11:42Z","timestamp":1768511502329,"version":"3.49.0"},"posted":{"date-parts":[[2024,4,20]]},"group-title":"Systems Biology","reference-count":97,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,4,20]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  Recent developments in cardiac macrophage biology have broadened our understanding of the critical functions of macrophages in the heart. As a result, there is further interest in understanding the independent contributions of distinct subsets of macrophage to cardiac development and function. Here, we demonstrate that genetic loss of interferon regulatory factor 8 (Irf8)-positive embryonic-derived macrophages significantly disrupts cardiac conduction, chamber function, and innervation in adult zebrafish. At 4 months post-fertilization (mpf), homozygous\n                  <jats:italic>\n                    irf8\n                    <jats:sup>st96\/st96<\/jats:sup>\n                  <\/jats:italic>\n                  mutants have significantly shortened atrial action potential duration and significant differential expression of genes involved in cardiac contraction. Functional\n                  <jats:italic>in vivo<\/jats:italic>\n                  assessments via electro- and echocardiograms at 12 mpf reveal that\n                  <jats:italic>irf8<\/jats:italic>\n                  mutants are arrhythmogenic and exhibit diastolic dysfunction and ventricular stiffening. To identify the molecular drivers of the functional disturbances in\n                  <jats:italic>irf8<\/jats:italic>\n                  null zebrafish, we perform single cell RNA sequencing and immunohistochemistry, which reveal increased leukocyte infiltration, epicardial activation, mesenchymal gene expression, and fibrosis.\n                  <jats:italic>Irf8<\/jats:italic>\n                  null hearts are also hyperinnervated and have aberrant axonal patterning, a phenotype not previously assessed in the context of cardiac macrophage loss. Gene ontology analysis supports a novel role for activated epicardial-derived cells (EPDCs) in promoting neurogenesis and neuronal remodeling\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Together, these data uncover significant cardiac abnormalities following embryonic macrophage loss and expand our knowledge of critical macrophage functions in heart physiology and governing homeostatic heart health.\n                <\/jats:p>","DOI":"10.1101\/2024.04.17.589909","type":"posted-content","created":{"date-parts":[[2024,4,20]],"date-time":"2024-04-20T23:25:11Z","timestamp":1713655511000},"source":"Crossref","is-referenced-by-count":0,"title":["Loss of developmentally derived Irf8+ macrophages promotes hyperinnervation and arrhythmia in the adult zebrafish heart"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7659-0612","authenticated-orcid":false,"given":"Shannon E.","family":"Paquette","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cliff 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