{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T10:36:07Z","timestamp":1762252567685,"version":"3.37.3"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,6,30]],"date-time":"2017-06-30T00:00:00Z","timestamp":1498780800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,6,30]],"date-time":"2017-06-30T00:00:00Z","timestamp":1498780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Corline Heparin Conjugate (CHC), a compound of multiple unfractionated heparin chains, coats cells with a glycocalyx-like layer and may inhibit (xeno)transplant-associated activation of the plasma cascade systems. Here, we investigated the use of CHC to protect WT and genetically modified (GTKO.hCD46.hTBM) pig aortic endothelial cells (PAEC) in two pig-to-human <jats:italic>in vitro<\/jats:italic> xenotransplantation settings. Model 1: incubation of untreated or hTNF\u03b1-treated PAEC with 10% human plasma induced complement C3b\/c and C5b-9 deposition, cellular activation and coagulation activation in WT and GTKO.hCD46.hTBM PAEC. Coating of untreated or hTNF\u03b1-treated PAEC with CHC (100\u2009\u00b5g\/ml) protected against human plasma-induced endothelial activation and damage. Model 2: PAEC were grown on microcarrier beads, coated with CHC, and incubated with non-anticoagulated whole human blood. Genetically modified PAEC significantly prolonged clotting time of human blood (115.0\u2009\u00b1\u200916.1\u2009min, p\u2009&lt;\u20090.001) compared to WT PAEC (34.0\u2009\u00b1\u20098.2\u2009min). Surface CHC significantly improved the human blood compatibility of PAEC, as shown by increased clotting time (WT: 84.3\u2009\u00b1\u200911.3\u2009min, p\u2009&lt;\u20090.001; GTKO.hCD46.hTBM: 146.2\u2009\u00b1\u200920.4\u2009min, p\u2009&lt;\u20090.05) and reduced platelet adhesion, complement activation, coagulation activation and inhibition of fibrinolysis. The combination of CHC coating and genetic modification provided the greatest compatibility with human blood, suggesting that pre-transplant perfusion of genetically modified porcine organs with CHC may benefit post-transplant xenograft function.<\/jats:p>","DOI":"10.1038\/s41598-017-04898-w","type":"journal-article","created":{"date-parts":[[2017,6,26]],"date-time":"2017-06-26T11:25:09Z","timestamp":1498476309000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Surface modification of pig endothelial cells with a branched heparin conjugate improves their compatibility with human blood"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2312-0374","authenticated-orcid":false,"given":"Anjan K.","family":"Bongoni","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evelyn","family":"Salvaris","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofia","family":"Nordling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikolai","family":"Klymiuk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eckhard","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David L.","family":"Ayares","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4179-8891","authenticated-orcid":false,"given":"Robert","family":"Rieben","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peetra U.","family":"Magnusson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9016-4954","authenticated-orcid":false,"given":"Peter J.","family":"Cowan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,6,30]]},"reference":[{"key":"4898_CR1","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1007\/s00424-007-0212-8","volume":"454","author":"S Reitsma","year":"2007","unstructured":"Reitsma, S., Slaaf, D. W., Vink, H., van Zandvoort, M. A. & oude Egbrink, M. G. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Archiv: European journal of physiology \n                           454, 345\u2013359 (2007).","journal-title":"Pflugers Archiv: European journal of physiology"},{"key":"4898_CR2","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1007\/s00281-011-0285-5","volume":"34","author":"VW van Hinsbergh","year":"2012","unstructured":"van Hinsbergh, V. W. Endothelium\u2013role in regulation of coagulation and inflammation. Seminars in immunopathology \n                           34, 93\u2013106 (2012).","journal-title":"Seminars in immunopathology"},{"key":"4898_CR3","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/nri2620","volume":"9","author":"PF Zipfel","year":"2009","unstructured":"Zipfel, P. F. & Skerka, C. Complement regulators and inhibitory proteins. Nature reviews. Immunology \n                           9, 729\u2013740 (2009).","journal-title":"Nature reviews. Immunology"},{"key":"4898_CR4","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1007\/s00395-010-0118-z","volume":"105","author":"BF Becker","year":"2010","unstructured":"Becker, B. F., Chappell, D. & Jacob, M. Endothelial glycocalyx and coronary vascular permeability: the fringe benefit. Basic research in cardiology \n                           105, 687\u2013701 (2010).","journal-title":"Basic research in cardiology"},{"key":"4898_CR5","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.1161\/01.ATV.0000085630.24353.3D","volume":"23","author":"AA Constantinescu","year":"2003","unstructured":"Constantinescu, A. A., Vink, H. & Spaan, J. A. Endothelial cell glycocalyx modulates immobilization of leukocytes at the endothelial surface. 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Critical pathways in cardiology \n                           9, 35\u201340 (2010).","journal-title":"Critical pathways in cardiology"},{"key":"4898_CR12","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1067\/mtc.2002.122551","volume":"124","author":"M Johnell","year":"2002","unstructured":"Johnell, M. et al. Coagulation, fibrinolysis, and cell activation in patients and shed mediastinal blood during coronary artery bypass grafting with a new heparin-coated surface. The Journal of thoracic and cardiovascular surgery \n                           124, 321\u2013332 (2002).","journal-title":"The Journal of thoracic and cardiovascular surgery"},{"key":"4898_CR13","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.thromres.2004.08.030","volume":"115","author":"K Christensen","year":"2005","unstructured":"Christensen, K., Larsson, R., Emanuelsson, H., Elgue, G. & Larsson, A. Improved blood compatibility of a stent graft by combining heparin coating and abciximab. 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The Journal of surgical research \n                           191, 455\u2013462 (2014).","journal-title":"The Journal of surgical research"},{"key":"4898_CR16","doi-asserted-by":"publisher","first-page":"1312","DOI":"10.1160\/TH14-09-0724","volume":"113","author":"S Nordling","year":"2015","unstructured":"Nordling, S. et al. Vascular repair utilising immobilised heparin conjugate for protection against early activation of inflammation and coagulation. Thrombosis and haemostasis \n                           113, 1312\u20131322 (2015).","journal-title":"Thrombosis and haemostasis"},{"key":"4898_CR17","doi-asserted-by":"publisher","first-page":"1871","DOI":"10.1097\/TP.0000000000001188","volume":"100","author":"AK Bongoni","year":"2016","unstructured":"Bongoni, A. K. et al. Transgenic Expression of Human Thrombomodulin Inhibits HMGB1-Induced Porcine Aortic Endothelial Cell Activation. 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Xenotransplantation \n                           8, 48\u201361 (2001).","journal-title":"Xenotransplantation"},{"key":"4898_CR24","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1097\/TP.0b013e3182a3a52b","volume":"96","author":"AK Bongoni","year":"2013","unstructured":"Bongoni, A. K. et al. Activation of the lectin pathway of complement in pig-to-human xenotransplantation models. Transplantation \n                           96, 791\u2013799 (2013).","journal-title":"Transplantation"},{"key":"4898_CR25","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1055\/s-0038-1653847","volume":"73","author":"HP Kohler","year":"1995","unstructured":"Kohler, H. P., Muller, M., Bombeli, T., Straub, P. W. & Haeberli, A. The suppression of the coagulation of nonanticoagulated whole blood in vitro by human umbilical endothelial cells cultivated on microcarriers is not dependent on protein C activation. Thrombosis and haemostasis \n                           73, 719\u2013724 (1995).","journal-title":"Thrombosis and haemostasis"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-04898-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-04898-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-04898-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T05:58:18Z","timestamp":1671775098000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-04898-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6,30]]},"references-count":25,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["4898"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-04898-w","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2017,6,30]]},"assertion":[{"value":"17 February 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 May 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 June 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"4450"}}