{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:09:33Z","timestamp":1790640573670,"version":"4.1.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2019,2,7]],"date-time":"2019-02-07T00:00:00Z","timestamp":1549497600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2019,2,7]],"date-time":"2019-02-07T00:00:00Z","timestamp":1549497600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2019,3]]},"abstract":"<jats:p>Normal liver sinusoidal endothelial cells (LSECs) promote quiescence of hepatic stellate cells (HSCs). Prior to fibrosis, LSECs undergo capillarization, which is permissive for HSC activation, the proximate event in hepatic fibrosis. The aims of this study were to elucidate the nature of and mechanisms leading to capillarization and to determine how LSECs promote HSC quiescence and why \u201ccapillarized LSECs\u201d lose control of HSC activation. The contribution of bone marrow (BM) endothelial progenitor cells to capillarization was identified using rats transplanted with transgenic enhanced green fluorescent protein\u2013positive BM. Shotgun proteomics and informatics were used to identify the LSEC mediator that maintains HSC quiescence. The study shows that capillarization is due to repair of injured LSECs by BM endothelial progenitors that engraft but fail to fully mature. Lack of maturation of BM\u2010derived LSECs is due to cell autonomous pathways that inhibit the nitric oxide pathway. We identify heparin binding epidermal growth factor\u2013like growth factor (HB\u2010EGF) as the signal that maintains HSC quiescence and show that immature LSECs are unable to shed HB\u2010EGF from the cytosolic membrane. Conclusion: Chronic liver injury can recruit BM progenitors of LSECs that engraft and fail to fully differentiate, which creates an environment that is permissive for hepatic fibrosis; elucidation of these early events in the fibrotic process will provide targets for treatment of hepatic fibrosis.<\/jats:p>","DOI":"10.1002\/hep.30227","type":"journal-article","created":{"date-parts":[[2018,8,24]],"date-time":"2018-08-24T01:19:27Z","timestamp":1535073567000},"page":"1259-1272","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":47,"title":["Incomplete Differentiation of Engrafted Bone Marrow Endothelial Progenitor Cells Initiates Hepatic Fibrosis in the Rat"],"prefix":"10.1097","volume":"69","author":[{"given":"Ana C.","family":"Maretti\u2010Mira","sequence":"first","affiliation":[{"name":"Division of Gastrointestinal and Liver Disease and the Research Center for Liver Disease,Keck Medicine of USC,Los Angeles,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangdong","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal and Liver Disease and the Research Center for Liver Disease,Keck Medicine of USC,Los Angeles,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal and Liver Disease and the Research Center for Liver Disease,Keck Medicine of USC,Los Angeles,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie D.","family":"DeLeve","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal and Liver Disease and the Research Center for Liver Disease,Keck Medicine of USC,Los Angeles,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2019,2,7]]},"reference":[{"key":"hep30227-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0016-5085(63)80130-4","article-title":"Capillarization of hepatic sinusoids in man","volume":"44","year":"1963","journal-title":"Gastroenterology"},{"key":"hep30227-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1002\/hep.22351","article-title":"Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence","volume":"48","year":"2008","journal-title":"Hepatology"},{"key":"hep30227-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1053\/j.gastro.2009.05.009","article-title":"Bone marrow progenitor cells repair rat hepatic sinusoidal endothelial cells after liver injury","volume":"137","year":"2009","journal-title":"Gastroenterology"},{"key":"hep30227-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1053\/j.gastro.2012.08.008","article-title":"Hepatic vascular endothelial growth factor regulates recruitment of rat liver sinusoidal endothelial cell progenitor cells","volume":"143","year":"2012","journal-title":"Gastroenterology"},{"key":"hep30227-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1172\/JCI58789","article-title":"Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats","volume":"122","year":"2012","journal-title":"J Clin Invest"},{"key":"hep30227-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"G739","DOI":"10.1152\/ajpgi.00056.2016","article-title":"VEGF\u2010sdf1 recruitment of CXCR6+ bone marrow progenitors of liver sinusoidal endothelial cells promotes rat liver regeneration","volume":"310","year":"2016","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"hep30227-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"G1204","DOI":"10.1152\/ajpgi.00302.2010","article-title":"Isolation of periportal, mid\u2010lobular and centrilobular rat liver sinusoidal endothelial cells enables study of zonated drug toxicity","volume":"299","year":"2010","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"hep30227-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrgastro.2017.38","article-title":"Mechanisms of hepatic stellate cell activation","volume":"14","year":"2017","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"hep30227-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1053\/j.gastro.2011.12.017","article-title":"Role of liver sinusoidal endothelial cell differentiation in progression and regression of rat hepatic fibrosis","volume":"142","year":"2012","journal-title":"Gastroenterology"},{"key":"hep30227-bib-0010-20241017","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.jhep.2016.04.018","article-title":"Sinusoidal communication in liver fibrosis and regeneration","volume":"65","year":"2016","journal-title":"J Hepatol"},{"key":"hep30227-bib-0011-20241017","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.jhep.2012.08.026","article-title":"The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial\u2010stellate cell deactivation induced by statins","volume":"58","year":"2013","journal-title":"J Hepatol"},{"key":"hep30227-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"G1187","DOI":"10.1152\/ajpgi.00229.2006","article-title":"Rat liver endothelial cells isolated by anti\u2010CD31 immunomagnetic separation lack fenestrae and sieve plates","volume":"291","year":"2006","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"hep30227-bib-0013-20241017","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1002\/hep.1840060505","article-title":"Phagocytosis, an unrecognized property of murine endothelial liver cells","volume":"6","year":"1986","journal-title":"Hepatology"},{"key":"hep30227-bib-0014-20241017","first-page":"D1063","article-title":". The Proteomics Identifications (PRIDE) database and associated tools: status in 2013","volume":"41","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"hep30227-bib-0015-20241017","doi-asserted-by":"crossref","first-page":"5002","DOI":"10.1182\/blood.V90.12.5002","article-title":"AC133, a novel marker for human hematopoietic stem and progenitor cells","volume":"90","year":"1997","journal-title":"Blood"},{"key":"hep30227-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"3106","DOI":"10.1182\/blood.V95.10.3106","article-title":"In vitro differentiation of endothelial cells from AC133\u2010positive progenitor cells","volume":"95","year":"2000","journal-title":"Blood"},{"key":"hep30227-bib-0017-20241017","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1182\/blood.V95.3.952.003k27_952_958","article-title":"Expression of VEGFR\u20102 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors","volume":"95","year":"2000","journal-title":"Blood"},{"key":"hep30227-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1016\/S0016-5085(99)70408-7","article-title":"Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat","volume":"117","year":"1999","journal-title":"Gastroenterology"},{"key":"hep30227-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/S0016-5085(98)70487-1","article-title":"Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension","volume":"114","year":"1998","journal-title":"Gastroenterology"},{"key":"hep30227-bib-0020-20241017","doi-asserted-by":"crossref","first-page":"G364","DOI":"10.1152\/ajpgi.00077.2013","article-title":"Genome\u2010wide transcriptome analysis identifies novel gene signatures implicated in human chronic liver disease","volume":"305","year":"2013","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"hep30227-bib-0021-20241017","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1161\/ATVBAHA.107.158154","article-title":"CD47: a new target in cardiovascular therapy","volume":"28","year":"2008","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"hep30227-bib-0022-20241017","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1111\/j.1537-2995.2008.01978.x","article-title":"ADAMTS13 binds to CD36: a potential mechanism for platelet and endothelial localization of ADAMTS13","volume":"49","year":"2009","journal-title":"Transfusion"},{"key":"hep30227-bib-0023-20241017","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1111\/j.1523-1755.2004.00780.x","article-title":"TGF\u2010beta induces proangiogenic and antiangiogenic factors via parallel but distinct Smad pathways","volume":"66","year":"2004","journal-title":"Kidney Int"},{"key":"hep30227-bib-0024-20241017","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s00441-007-0387-5","article-title":"Involvement of signaling of VEGF and TGF\u2010beta in differentiation of sinusoidal endothelial cells during culture of fetal rat liver cells","volume":"329","year":"2007","journal-title":"Cell Tissue Res"},{"key":"hep30227-bib-0025-20241017","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.bbrc.2013.05.097","article-title":"Conditional loss of heparin\u2010binding EGF\u2010like growth factor results in enhanced liver fibrosis after bile duct ligation in mice","volume":"437","year":"2013","journal-title":"Biochem Biophys Res Commun"},{"key":"hep30227-bib-0026-20241017","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/labinvest.2012.3","article-title":"Heparin\u2010binding epidermal growth factor\u2013like growth factor suppresses experimental liver fibrosis in mice","volume":"92","year":"2012","journal-title":"Lab Invest"},{"key":"hep30227-bib-0027-20241017","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/jth.12412","article-title":"Human liver sinusoidal endothelial cells but not hepatocytes contain factor VIII","volume":"12","year":"2014","journal-title":"J Thromb Haemost"},{"key":"hep30227-bib-0028-20241017","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1111\/febs.13665","article-title":"TGF\u2010beta signalling and liver disease","volume":"283","year":"2016","journal-title":"FEBS J"},{"key":"hep30227-bib-0029-20241017","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1093\/emboj\/21.7.1743","article-title":"Balancing the activation state of the endothelium via two distinct TGF\u2010beta type I receptors","volume":"21","year":"2002","journal-title":"EMBO J"},{"key":"hep30227-bib-0030-20241017","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1053\/j.gastro.2011.12.017","article-title":"Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats","volume":"142","year":"2012","journal-title":"Gastroenterology"},{"key":"hep30227-bib-0031-20241017","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1111\/liv.12231","article-title":"The CD47\u2010binding peptide of thrombospondin\u20101 induces defenestration of liver sinusoidal endothelial cells","volume":"33","year":"2013","journal-title":"Liver Int"},{"key":"hep30227-bib-0032-20241017","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1093\/cvr\/cvq218","article-title":"Thrombospondin\u20101 supports blood pressure by limiting eNOS activation and endothelial\u2010dependent vasorelaxation","volume":"88","year":"2010","journal-title":"Cardiovasc Res"},{"key":"hep30227-bib-0033-20241017","doi-asserted-by":"crossref","first-page":"15404","DOI":"10.1074\/jbc.M701638200","article-title":"Thrombospondin\u20101 inhibits nitric oxide signaling via CD36 by inhibiting myristic acid uptake","volume":"282","year":"2007","journal-title":"J Biol Chem"},{"key":"hep30227-bib-0034-20241017","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1080\/08977190500095980","article-title":"Characterization of intracellular pathways leading to coinduction of thrombospondin\u20101 and TGF\u2010beta1 expression in rat hepatic stellate cells","volume":"23","year":"2005","journal-title":"Growth Factors"},{"key":"hep30227-bib-0035-20241017","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1111\/j.1538-7836.2006.01893.x","article-title":"Increased ADAMTS\u201013 proteolytic activity in rat hepatic stellate cells upon activation in vitro and in vivo","volume":"4","year":"2006","journal-title":"J Thromb Haemost"},{"key":"hep30227-bib-0036-20241017","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1002\/hep.24800","article-title":"Thrombospondin\u20101 is a novel negative regulator of liver regeneration after partial hepatectomy through transforming growth factor\u2010beta1 activation in mice","volume":"55","year":"2012","journal-title":"Hepatology"},{"key":"hep30227-bib-0037-20241017","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s13238-012-2006-9","article-title":"Overexpression of sigma\u20101 receptor inhibits ADAM10 and ADAM17 mediated shedding in vitro","volume":"3","year":"2012","journal-title":"Protein Cell"},{"key":"hep30227-bib-0038-20241017","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.yexcr.2016.10.004","article-title":"Overexpression of soluble ADAM33 promotes a hypercontractile phenotype of the airway smooth muscle cell in rat","volume":"349","year":"2016","journal-title":"Exp Cell Res"},{"key":"hep30227-bib-0039-20241017","doi-asserted-by":"crossref","first-page":"e0158995","DOI":"10.1371\/journal.pone.0158995","article-title":"Comprehensive analysis of genome rearrangements in eight human malignant tumor tissues","volume":"11","year":"2016","journal-title":"PLoS One"},{"key":"hep30227-bib-0040-20241017","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1083\/jcb.201209151","article-title":"Notch increases the shedding of HB\u2010EGF by ADAM12 to potentiate invadopodia formation in hypoxia","volume":"201","year":"2013","journal-title":"J Cell Biol"},{"key":"hep30227-bib-0041-20241017","doi-asserted-by":"crossref","first-page":"2452","DOI":"10.1038\/sj.onc.1209287","article-title":"Full\u2010length ADAMTS\u20101 and the ADAMTS\u20101 fragments display pro\u2010 and antimetastatic activity, respectively","volume":"25","year":"2006","journal-title":"Oncogene"},{"key":"hep30227-bib-0042-20241017","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1161\/ATVBAHA.111.241257","article-title":"Metalloproteinase processing of HBEGF is a proximal event in the response of human aortic endothelial cells to oxidized phospholipids","volume":"32","year":"2012","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"hep30227-bib-0043-20241017","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/bs.ctdb.2016.08.008","article-title":"TBX5","volume":"122","year":"2017","journal-title":"Current topics in developmental biology"},{"key":"hep30227-bib-0044-20241017","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/bs.ctdb.2016.08.002","article-title":"Tbx1","volume":"122","year":"2017","journal-title":"Curr Top Dev Biol"},{"key":"hep30227-bib-0045-20241017","first-page":"77","article-title":"MicroRNAs and fetal brain development: implications for ethanol teratology during the second trimester period of neurogenesis","volume":"3","year":"2012","journal-title":"Front Genet"},{"key":"hep30227-bib-0046-20241017","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/nm.4035","article-title":"Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis","volume":"22","year":"2016","journal-title":"Nat Med"},{"key":"hep30227-bib-0047-20241017","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.2353\/ajpath.2008.080433","article-title":"Pericytes and perivascular fibroblasts are the primary source of collagen\u2010producing cells in obstructive fibrosis of the kidney","volume":"173","year":"2008","journal-title":"Am J Pathol"},{"key":"hep30227-bib-0048-20241017","doi-asserted-by":"crossref","first-page":"2605","DOI":"10.1002\/art.22035","article-title":"Bone marrow endothelial progenitors are defective in systemic sclerosis","volume":"54","year":"2006","journal-title":"Arthritis Rheum"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.30227","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201903000-00032","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T23:34:27Z","timestamp":1729208067000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201903000-00032"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,7]]},"references-count":48,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2019]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.30227","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,7]]},"assertion":[{"value":"2018-05-09","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-08-20","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}