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The Junctional Adhesion Molecule A (JAM\u2010A) is a crucial regulator of leukocyte extravasation and is upregulated in human viral fibrosis. Reduced shear stress within hepatic sinusoids and the specific phenotype of liver sinusoidal endothelial cells (LSEC) cumulate in differing adhesion characteristics during liver fibrosis. The aim of this study was to define the functional role of cell\u2010specific adhesion molecule JAM\u2010A during hepatic fibrogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Complete, conditional (intestinal epithelial; endothelial) and bone marrow chimeric <jats:italic>Jam\u2010a<\/jats:italic> knockout animals and corresponding C57Bl\/6 wild\u2010type animals were treated with carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>, 6\u00a0weeks). For functional analyses of JAM\u2010A, comprehensive in vivo studies, co\u2010culture models and flow\u2010based adhesion assays were performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Complete and bone marrow\u2010derived <jats:italic>Jam\u2010a<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> animals showed aggravated fibrosis with increased non\u2010sinusoidal, perivascular accumulation of CD11b<jats:sup>+<\/jats:sup>F4\/80<jats:sup>+<\/jats:sup> monocyte\u2010derived macrophages in contrast to wild\u2010type mice. Despite being associated with disturbed epithelial barrier function, an intestinal epithelial <jats:italic>Jam\u2010a<\/jats:italic> knockout did not affect fibrogenesis. In endothelial\u2010specific <jats:italic>Jam\u2010a<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> animals, liver fibrosis was aggravated alongside sinusoid capillarization and hepatic stellate cell (HSC) activation. HSC activation is induced via <jats:italic>Jam\u2010a<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> LSEC\u2010derived secretion of soluble factors. Sinusoid CD31 expression and hedgehog gene signalling were increased, but leukocyte infiltration and adhesion to LSECs remained unaffected.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our models decipher cell\u2010specific JAM\u2010A to exert crucial functions during hepatic fibrogenesis. JAM\u2010A on bone marrow\u2010derived cells regulates non\u2010sinusoidal vascular immune cell recruitment, while endothelial JAM\u2010A controls liver sinusoid capillarization and HSC quiescence.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15187","type":"journal-article","created":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T10:56:36Z","timestamp":1644231396000},"page":"1185-1203","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["<scp>JAM\u2010A<\/scp> is a multifaceted regulator in hepatic fibrogenesis, supporting <scp>LSEC<\/scp> integrity and stellate cell quiescence"],"prefix":"10.1111","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7429-7412","authenticated-orcid":false,"given":"Jonathan F.","family":"Brozat","sequence":"first","affiliation":[{"name":"Department of Internal Medicine III RWTH Aachen University Hospital, RWTH Aachen  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa F.","family":"Brandt","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III RWTH Aachen University Hospital, RWTH Aachen  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Stark","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III RWTH Aachen University Hospital, RWTH Aachen  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Fischer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III RWTH Aachen University Hospital, RWTH Aachen  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa H.","family":"Wirtz","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III RWTH Aachen University Hospital, RWTH Aachen  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Fla\u00dfhove","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III RWTH Aachen University Hospital, RWTH Aachen  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron N.","family":"Rodenhausen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III RWTH Aachen University Hospital, RWTH Aachen  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Vajen","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Laboratory, Division of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty Heinrich\u2010Heine\u2010University  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra C. 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