{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:55:21Z","timestamp":1753890921828,"version":"3.41.2"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T00:00:00Z","timestamp":1736899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Macrophages are known to support cardiac development and homeostasis, contributing to tissue remodeling and repair in the adult heart. However, it remains unclear whether embryonic macrophages also respond to abnormalities in the developing heart. Previously, we reported that the structural protein Sorbs2 promotes the development of the second heart field, with its deficiency resulting in atrial septal defects (ASD). In analyzing RNA-seq data, we noted an upregulation of macrophage-related genes in <jats:italic>Sorbs2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> hearts. Immunostaining and lineage-tracing confirmed an increase in macrophage numbers, underscoring a macrophage response to myocardial abnormalities. Partial depletion of macrophages led to downregulation of genes involved in lipid metabolism, muscle development and organ regeneration, alongside upregulation of genes associated with DNA damage-induced senescence and cardiomyopathy. Additionally, a non-significant increase in septal defects in macrophage-depleted <jats:italic>Sorbs2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> hearts suggests a potential reparative function for macrophages in maintaining structural integrity. Valve formation, however, remained unaffected. Our findings suggest that embryonic macrophages might sense abnormalities in embryonic cardiomyocytes and could adaptively support cardiac structure and function development in response to myocardial abnormalities.<\/jats:p>","DOI":"10.3389\/fgene.2024.1525931","type":"journal-article","created":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T06:13:22Z","timestamp":1736921602000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Increased cardiac macrophages in Sorbs2-deficient hearts: revealing a potential role for macrophage in responding to embryonic myocardial abnormalities"],"prefix":"10.3389","volume":"15","author":[{"given":"Beibei","family":"Hu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangyang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shanshan","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qin","family":"Gong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junjie","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongjun","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fei","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1007\/s00246-019-02164-6","article-title":"Phases and mechanisms of embryonic cardiomyocyte proliferation and ventricular wall morphogenesis","volume":"40","author":"Barak","year":"2019","journal-title":"Pediatr. Cardiol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"dev194563","DOI":"10.1242\/dev.194563","article-title":"Tissue-resident macrophages regulate lymphatic vessel growth and patterning in the developing heart","volume":"148","author":"Cahill","year":"2021","journal-title":"Development"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s12276-019-0269-4","article-title":"Macrophages in cardiac repair: environmental cues and therapeutic strategies","volume":"51","author":"De Couto","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"873264","DOI":"10.3389\/fcell.2022.873264","article-title":"Non-cardiomyocytes in the heart in embryo development, health, and disease, a single-cell perspective","volume":"10","author":"Ding","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e017055","DOI":"10.1161\/JAHA.119.017055","article-title":"Knockout of SORBS2 protein disrupts the structural integrity of intercalated disc and manifests features of arrhythmogenic cardiomyopathy","volume":"9","author":"Ding","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"B6","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.immuni.2013.11.019","article-title":"Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation","volume":"40","author":"Epelman","year":"2014","journal-title":"Immunity"},{"key":"B7","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1007\/s00418-020-01934-1","article-title":"Potential functions of embryonic cardiac macrophages in angiogenesis, lymphangiogenesis and extracellular matrix remodeling","volume":"155","author":"Gula","year":"2021","journal-title":"Histochem Cell Biol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1086","DOI":"10.1161\/CIRCRESAHA.119.315862","article-title":"Cardiomyocyte maturation: new phase in development","volume":"126","author":"Guo","year":"2020","journal-title":"Circ. Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/s41576-019-0169-4","article-title":"Mechanisms of early placental development in mouse and humans","volume":"21","author":"Hemberger","year":"2020","journal-title":"Nat. Rev. Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1002\/gene.20162","article-title":"In vivo genetic ablation by Cre-mediated expression of diphtheria toxin fragment A","volume":"43","author":"Ivanova","year":"2005","journal-title":"Genesis"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1498","DOI":"10.1161\/CIRCRESAHA.115.308270","article-title":"Primitive embryonic macrophages are required for coronary development and maturation","volume":"118","author":"Leid","year":"2016","journal-title":"Circulation Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"e67481","DOI":"10.7554\/eLife.67481","article-title":"SORBS2 is a genetic factor contributing to cardiac malformation of 4q deletion syndrome patients","volume":"10","author":"Liang","year":"2021","journal-title":"eLife"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1096\/fasebj.2020.34.s1.07385","article-title":"Loss of SORBS2 in cardiomyocytes leads to dilated left ventricle cardiomyopathy in mice","volume":"34","author":"Mclendon","year":"2020","journal-title":"FASEB J."},{"key":"B14","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1016\/j.devcel.2016.11.012","article-title":"Myocardial VHL-HIF signaling controls an embryonic metabolic switch essential for cardiac maturation","volume":"39","author":"Menendez-Montes","year":"2016","journal-title":"Dev. Cell"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1007\/s10741-021-10156-z","article-title":"Multiple roles of cardiac macrophages in heart homeostasis and failure","volume":"27","author":"Moskalik","year":"2022","journal-title":"Heart Fail Rev."},{"key":"B16","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1002\/dvg.20335","article-title":"A global double-fluorescent Cre reporter mouse","volume":"45","author":"Muzumdar","year":"2007","journal-title":"Genesis"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e29330","DOI":"10.7554\/eLife.29330","article-title":"Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis","volume":"6","author":"Nakano","year":"2017","journal-title":"Elife"},{"key":"B18","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.ppedcard.2011.02.002","article-title":"Bioenergetics, mitochondria, and cardiac myocyte differentiation","volume":"31","author":"Porter","year":"2011","journal-title":"Prog. Pediatr. Cardiol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1016\/j.devcel.2019.01.021","article-title":"Endocardially derived macrophages are essential for valvular remodeling","volume":"48","author":"Shigeta","year":"2019","journal-title":"Dev. Cell"},{"key":"B20","doi-asserted-by":"publisher","first-page":"165881","DOI":"10.1016\/j.bbadis.2020.165881","article-title":"Metabolic environment in vivo as a blueprint for differentiation and maturation of human stem cell-derived cardiomyocytes","volume":"1866","author":"Slaats","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"B21","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1111\/j.1749-6632.2009.05089.x","article-title":"The role of mechanical forces in the torsional component of cardiac looping","volume":"1188","author":"Taber","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1093\/cvr\/cvs270","article-title":"Early cardiac development: a view from stem cells to embryos","volume":"96","author":"Van Vliet","year":"2012","journal-title":"Cardiovasc Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"17542","DOI":"10.1074\/jbc.272.28.17542","article-title":"ArgBP2, a multiple Src homology 3 domain-containing, Arg\/Abl-interacting protein, is phosphorylated in v-Abl-transformed cells and localized in stress fibers and cardiocyte Z-disks","volume":"272","author":"Wang","year":"1997","journal-title":"J. Biol. Chem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"108041","DOI":"10.1016\/j.celrep.2020.108041","article-title":"Efficient strategies for microglia replacement in the central nervous system","volume":"32","author":"Xu","year":"2020","journal-title":"Cell Rep."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2366","DOI":"10.21037\/tp-21-297","article-title":"Genetics of congenital heart disease: a narrative review of recent advances and clinical implications","volume":"10","author":"Yasuhara","year":"2021","journal-title":"Transl. Pediatr."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2247","DOI":"10.1523\/JNEUROSCI.2528-15.2016","article-title":"Impaired Dendritic Development and Memory in Sorbs2 Knock-Out Mice","volume":"36","author":"Zhang","year":"2016","journal-title":"J. Neurosci."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2024.1525931\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T06:13:27Z","timestamp":1736921607000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2024.1525931\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,15]]},"references-count":26,"alternative-id":["10.3389\/fgene.2024.1525931"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2024.1525931","relation":{},"ISSN":["1664-8021"],"issn-type":[{"type":"electronic","value":"1664-8021"}],"subject":[],"published":{"date-parts":[[2025,1,15]]},"article-number":"1525931"}}