{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:03:16Z","timestamp":1785423796669,"version":"3.56.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"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. Cardiovasc. Med."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The objective of this study was to gain insight into the molecular mechanisms leading to early degeneration of decellularized homografts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Formalin-fixed and paraffin-embedded tissues from fresh explanted decellularized aortic (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20097) and pulmonary (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20098) valves were used. RNA was isolated and analyzed using panel-based transcriptomics, focusing on fibrosis- and inflammation-related genes. Differentially expressed genes were used as input parameters for biological pathway analysis using the Gene Ontology Biological Process and Hallmark databanks. Formalin-fixed and paraffin-embedded tissues from freshly explanted healthy donor aortic (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20097) and pulmonary valves (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20098) were used as controls.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our analysis revealed 56 differentially expressed genes in decellularized aortic valves compared to donor aortic valves, of which 21 and 35 were up- and downregulated, respectively. Decellularized pulmonary valves showed 115 differentially expressed genes compared to donor pulmonary valves, 66 of which were up- and 49 downregulated. In both decellularized aortic and pulmonary valve explants, we found increased expression of fibrosis-, inflammation-, and endothelium-related genes and a decreased expression of genes encoding for complement factors in line with the observed biological pathway activity patterns.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We present a comprehensive transcriptome analysis of explanted decellularized heart valve homografts providing insights into the biological processes leading to continued degeneration and ultimately loss of function. The degeneration of decellularized homografts is driven by inflammation, fibrosis, and extracellular matrix (ECM) remodelling, reinforced by ongoing oxidative stress rather than by a mainly complement-driven humoral immune response.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcvm.2026.1865343","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:06:34Z","timestamp":1785420394000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The molecular signature of degeneration in explanted decellularized allogeneic heart valves"],"prefix":"10.3389","volume":"13","author":[{"given":"Allison D.","family":"Seidel","sequence":"first","affiliation":[{"name":"Institute of Pathology, Hannover Medical School","place":["Hannover, Germany"]},{"name":"Department of Cardiothoracic, Transplant, and Vascular Surgery, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"R\u00fcckoldt","sequence":"additional","affiliation":[{"name":"Biomedical Research in Endstage and Obstructive Lung Disease Hanover (BREATH), German Center for Lung Research (DZL)","place":["Hannover, Germany"]},{"name":"Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Werlein","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mareike","family":"Knoll","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Petzold","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Hannover Medical School","place":["Hannover, Germany"]},{"name":"Biomedical Research in Endstage and Obstructive Lung Disease Hanover (BREATH), German Center for Lung Research (DZL)","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina","family":"Engelhardt","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Riehle","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Horke","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic, Transplant, and Vascular Surgery, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry","family":"Bobylev","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic, Transplant, and Vascular Surgery, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murat","family":"Avsar","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic, Transplant, and Vascular Surgery, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samir","family":"Sarikouch","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic, Transplant, and Vascular Surgery, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lavinia","family":"Neubert","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Hannover Medical School","place":["Hannover, Germany"]},{"name":"Biomedical Research in Endstage and Obstructive Lung Disease Hanover (BREATH), German Center for Lung Research (DZL)","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan C.","family":"Kamp","sequence":"additional","affiliation":[{"name":"Biomedical Research in Endstage and Obstructive Lung Disease Hanover (BREATH), German Center for Lung Research (DZL)","place":["Hannover, Germany"]},{"name":"Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1097\/CRD.0000000000000519","article-title":"Immunogenicity of homologous heart valves: mechanisms and future considerations","volume":"32","author":"Vogel","year":"2024","journal-title":"Cardiol Rev"},{"key":"B2","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/0741-5214(84)90197-6","article-title":"Detergent-extracted small-diameter vascular prostheses","volume":"1","author":"Malone","year":"1984","journal-title":"J Vasc Surg"},{"key":"B3","doi-asserted-by":"publisher","first-page":"I132","DOI":"10.1161\/CIRCULATIONAHA.105.001065","article-title":"Clinical application of tissue engineered human heart valves using autologous progenitor cells","volume":"114","author":"Cebotari","year":"2006","journal-title":"Circulation"},{"key":"B4","doi-asserted-by":"publisher","first-page":"ezag087","DOI":"10.1093\/ejcts\/ezag087","article-title":"20-year Experience with decellularized pulmonary homografts for pulmonary valve replacement","volume":"68","author":"Sarikouch","year":"2026","journal-title":"Eur J Cardiothorac Surg"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e35","DOI":"10.1161\/CIR.0000000000000932","article-title":"2020 ACC\/AHA guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology\/American Heart Association joint committee on clinical practice guidelines","volume":"143","author":"Otto","year":"2021","journal-title":"Circulation"},{"key":"B6","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1016\/j.athoracsur.2015.03.105","article-title":"Very long-term outcomes of the carpentier-edwards perimount aortic valve in patients aged 60 or younger","volume":"100","author":"Bourguignon","year":"2015","journal-title":"Ann Thorac Surg"},{"key":"B7","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1093\/ejcts\/ezx396","article-title":"Impact of T-cell-mediated immune response on xenogeneic heart valve transplantation: short-term success and mid-term failure","volume":"53","author":"Biermann","year":"2018","journal-title":"Eur J Cardiothorac Surg"},{"key":"B8","first-page":"334","article-title":"The homograft aortic valve: a 29-year, 99.3% follow-up of 1,022 valve replacements","volume":"10","author":"O\u2019Brien","year":"2001","journal-title":"J Heart Valve Dis"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1016\/S0003-4975(02)03885-7","article-title":"Immunology and failure of valved allografts in children","volume":"74","author":"Shaddy","year":"2002","journal-title":"Ann Thorac Surg"},{"key":"B10","doi-asserted-by":"publisher","first-page":"S71","DOI":"10.1016\/0003-4975(95)00289-W","article-title":"Accelerated degeneration of allografts in the first two years of life","volume":"60","author":"Yankah","year":"1995","journal-title":"Ann Thorac Surg"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1093\/ejcts\/ezaa100","article-title":"Early results from a prospective, single-arm European trial on decellularized allografts for aortic valve replacement: the ARISE study and ARISE registry data","volume":"58","author":"Horke","year":"2020","journal-title":"Eur J Cardiothorac Surg"},{"key":"B12","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1093\/ejcts\/ezaa393","article-title":"Residual immune response towards decellularized homografts may be highly individual","volume":"59","author":"Ebken","year":"2021","journal-title":"Eur J Cardiothorac Surg"},{"key":"B13","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1080\/01478885.2024.2446038","article-title":"Resolving the bone - optimizing decalcification in spatial transcriptomics and molecular pathology","volume":"48","author":"Wang","year":"2025","journal-title":"J Histotechnol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.1038\/s41379-020-0503-6","article-title":"Effect of decalcification protocols on immunohistochemistry and molecular analyses of bone samples","volume":"33","author":"Miquelestorena-Standley","year":"2020","journal-title":"Mod Pathol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"Clusterprofiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1755","DOI":"10.1016\/j.athoracsur.2003.11.049","article-title":"Histopathologic findings in a novel decellularized pulmonary homograft: an autopsy study","volume":"79","author":"Sayk","year":"2005","journal-title":"Ann Thorac Surg"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1089\/ten.tea.2013.0316","article-title":"Early systemic cellular immune response in children and young adults receiving decellularized fresh allografts for pulmonary valve replacement","volume":"20","author":"Neumann","year":"2014","journal-title":"Tissue Eng Part A"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1338","DOI":"10.1161\/CIRCULATIONAHA.118.037953","article-title":"CXCL12 Derived from endothelial cells promotes atherosclerosis to drive coronary artery disease","volume":"139","author":"D\u00f6ring","year":"2019","journal-title":"Circulation"},{"key":"B19","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1038\/s42003-023-04706-4","article-title":"PIEZO1 And PECAM1 interact at cell-cell junctions and partner in endothelial force sensing","volume":"6","author":"Chuntharpursat-Bon","year":"2023","journal-title":"Commun Biol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1097\/MOH.0000000000000239","article-title":"Endothelial functions of platelet\/endothelial cell adhesion molecule-1 (CD31)","volume":"23","author":"Lertkiatmongkol","year":"2016","journal-title":"Curr Opin Hematol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1093\/eurheartj\/ehac787","article-title":"Have we found the missing link between inflammation, fibrosis, and calcification in calcific aortic valve disease?","volume":"44","author":"Martin","year":"2023","journal-title":"Eur Heart J"},{"key":"B22","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1093\/eurheartj\/ehac818","article-title":"Sortilin enhances fibrosis and calcification in aortic valve disease by inducing interstitial cell heterogeneity","volume":"44","author":"Iqbal","year":"2023","journal-title":"Eur Heart J"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1039\/C9BM01780A","article-title":"Regulation of decellularized matrix mediated immune response","volume":"8","author":"Chakraborty","year":"2020","journal-title":"Biomater Sci"},{"key":"B24","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s11357-017-9959-9","article-title":"The impact of aging on cardiac extracellular matrix","volume":"39","author":"Meschiari","year":"2017","journal-title":"Geroscience"},{"key":"B25","doi-asserted-by":"publisher","first-page":"114240","DOI":"10.1016\/j.addr.2022.114240","article-title":"Matrikines as mediators of tissue remodelling","volume":"185","author":"Jariwala","year":"2022","journal-title":"Adv Drug Deliv Rev"},{"key":"B26","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1186\/s12935-025-03995-5","article-title":"Role of human myocyte enhancer factor 2 (MEF2) proteins in cancer: structural insights, functional diversity, and regulatory mechanisms","volume":"25","author":"Khandelwal","year":"2025","journal-title":"Cancer Cell Int"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.3724\/abbs.2025163","article-title":"Myocyte enhancer factor 2a orchestrates vascular redox homeostasis via direct transcriptional activation of SIRT1","volume":"58","author":"Liu","year":"2025","journal-title":"Acta Biochim Biophys Sin (Shanghai)"},{"key":"B28","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.redox.2015.07.008","article-title":"Antioxidant responses and cellular adjustments to oxidative stress","volume":"6","author":"Espinosa-Diez","year":"2015","journal-title":"Redox Biol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1042\/BST20230860","article-title":"Modification of extracellular matrix proteins by oxidants and electrophiles","volume":"52","author":"Yang-Jensen","year":"2024","journal-title":"Biochem Soc Trans"},{"key":"B30","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1089\/adt.2012.474","article-title":"Extracellular matrix remodeling: the common denominator in connective tissue diseases. Possibilities for evaluation and current understanding of the matrix as more than a passive architecture, but a key player in tissue failure","volume":"11","author":"Karsdal","year":"2013","journal-title":"Assay Drug Dev Technol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1002\/j.2040-4603.2016.tb00724.x","article-title":"Heart valve biomechanics and underlying mechanobiology","volume":"6","author":"Ayoub","year":"2016","journal-title":"Compr Physiol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"829120","DOI":"10.3389\/fcvm.2022.829120","article-title":"Understanding pulmonary autograft remodeling after the ross procedure: stick to the facts","volume":"9","author":"Van Hoof","year":"2022","journal-title":"Front Cardiovasc Med"},{"key":"B33","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1016\/j.actbio.2017.03.026","article-title":"Quantification and comparison of the mechanical properties of four human cardiac valves","volume":"54","author":"Pham","year":"2017","journal-title":"Acta Biomater"},{"key":"B34","doi-asserted-by":"publisher","first-page":"760635","DOI":"10.3389\/fcvm.2021.760635","article-title":"Residual bioprosthetic valve immunogenicity: forgotten, not lost","volume":"8","author":"Human","year":"2022","journal-title":"Front Cardiovasc Med"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2026.1865343\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:06:35Z","timestamp":1785420395000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2026.1865343\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,30]]},"references-count":34,"alternative-id":["10.3389\/fcvm.2026.1865343"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2026.1865343","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,30]]},"article-number":"1865343"}}