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How multinucleation\n                    <jats:italic>per se<\/jats:italic>\n                    contributes to functional specialization of mature mononuclear macrophages remains poorly understood in humans. Here, we integrate comparative transcriptomics with functional assays in purified mature mononuclear and multinucleated human osteoclasts, LGCs and FBGCs. Strikingly, in all three types of MGCs, multinucleation causes a pronounced downregulation of macrophage identity. We show enhanced lysosome\u2010mediated intracellular iron homeostasis promoting MGC formation. The transition from mononuclear to multinuclear state is accompanied by cell specialization specific to each polykaryon. Enhanced phagocytic and mitochondrial function associate with FBGCs and osteoclasts, respectively. Moreover, human LGCs preferentially express B7\u2010H3 (CD276) and can form granuloma\u2010like clusters\n                    <jats:italic>in\u00a0vitro<\/jats:italic>\n                    , suggesting that their multinucleation potentiates T cell activation. These findings demonstrate how cell\u2013cell fusion and multinucleation reset human macrophage identity as part of\u00a0an advanced maturation step that confers MGC\u2010specific functionality.\n                  <\/jats:p>","DOI":"10.15252\/embr.202256310","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T03:59:17Z","timestamp":1672804757000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Multinucleation resets human macrophages for specialized functions at the expense of their identity"],"prefix":"10.1038","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3155-7509","authenticated-orcid":false,"given":"Kourosh","family":"Ahmadzadeh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margot","family":"Vanoppen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eline","family":"Bernaerts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong\u2010Hun","family":"Ko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Mitera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8852-915X","authenticated-orcid":false,"given":"Christy","family":"Maksoudian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3402-3927","authenticated-orcid":false,"given":"Bella B","family":"Manshian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2390-3133","authenticated-orcid":false,"given":"Stefaan","family":"Soenen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos D","family":"Rose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham R","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J H Duncan","family":"Bassett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9685-6836","authenticated-orcid":false,"given":"Patrick","family":"Matthys","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6426-8845","authenticated-orcid":false,"given":"Carine","family":"Wouters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5170-2606","authenticated-orcid":false,"given":"Jacques","family":"Behmoaras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,1,4]]},"reference":[{"key":"BFEMBR202256310_CR1","first-page":"164","volume":"84","author":"DO Adams","year":"1976","unstructured":"Adams DO (1976) The granulomatous inflammatory response. 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