{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T10:08:25Z","timestamp":1761646105673,"version":"build-2065373602"},"reference-count":61,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,20]],"date-time":"2021-08-20T00:00:00Z","timestamp":1629417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Transplantation of xenogenic porcine chondrocytes could represent a future strategy for the treatment of human articular cartilage defects. Major obstacles are humoral and cellular rejection processes triggered by xenogenic epitopes like \u03b1-1,3-Gal and Neu5Gc. Besides knockout (KO) of genes responsible for the biosynthesis of respective epitopes (GGTA1 and CMAH), transgenic expression of human complement inhibitors and anti-apoptotic as well as anti-inflammatory factors (CD46, CD55, CD59, TNFAIP3 and HMOX1) could synergistically prevent hyperacute xenograft rejection. Therefore, chondrocytes from different strains of single- or multi-genetically modified pigs were characterized concerning their protection from xenogeneic complement activation. Articular chondrocytes were isolated from the knee joints of WT, GalTKO, GalT\/CMAH-KO, human CD59\/CD55\/\/CD46\/TNFAIP3\/HMOX1-transgenic (TG), GalTKO\/TG and GalT\/CMAHKO\/TG pigs. The tissue-specific effectiveness of the genetic modifications was tested on gene, protein and epitope expression level or by functional assays. After exposure to 20% and 40% normal human serum (NHS), deposition of C3b\/iC3b\/C3c and formation of the terminal complement complex (TCC, C5b-9) was quantified by specific cell ELISAs, and generation of the anaphylatoxin C5a by ELISA. Chondrocyte lysis was analyzed by Trypan Blue Exclusion Assay. In all respective KO variants, the absence of \u03b1 -1,3-Gal and Neu5Gc epitope was verified by FACS analysis. In chondrocytes derived from TG animals, expression of CD55 and CD59 could be confirmed on gene and protein level, TNFAIP3 on gene expression level as well as by functional assays and CD46 only on gene expression level whereas transgenic HMOX1 expression was not evident. Complement activation in the presence of NHS indicated mainly effective although incomplete protection against C3b\/iC3b\/C3c deposition, C5a-generation and C5b-9 formation being lowest in single GalTKO. Chondrocyte viability under exposure to NHS was significantly improved even by single GalTKO and completely preserved by all other variants including TG chondrocytes without KO of xenoepitopes.<\/jats:p>","DOI":"10.3390\/cells10082152","type":"journal-article","created":{"date-parts":[[2021,8,22]],"date-time":"2021-08-22T21:42:12Z","timestamp":1629668532000},"page":"2152","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["New Insights into Xenotransplantation for Cartilage Repair: Porcine Multi-Genetically Modified Chondrocytes as a Promising Cell Source"],"prefix":"10.3390","volume":"10","author":[{"given":"Hanna","family":"Tritschler","sequence":"first","affiliation":[{"name":"Division for Biochemistry of Joint and Connective Tissue Diseases, Department of Orthopedics, University of Ulm, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4926-7334","authenticated-orcid":false,"given":"Konrad","family":"Fischer","sequence":"additional","affiliation":[{"name":"Chair of Livestock Biotechnology, School of Life Sciences Weihenstephan, Technische Universit\u00e4t M\u00fcnchen, 85354 Freising, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jochen","family":"Seissler","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik IV, Diabetes Zentrum\u2014Campus Innenstadt, Klinikum der Ludwig-Maximilians-Universit\u00e4t, 80336 M\u00fcnchen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5834-3730","authenticated-orcid":false,"given":"J\u00f6rg","family":"Fiedler","sequence":"additional","affiliation":[{"name":"Division for Biochemistry of Joint and Connective Tissue Diseases, Department of Orthopedics, University of Ulm, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8060-2076","authenticated-orcid":false,"given":"Rebecca","family":"Halbgebauer","sequence":"additional","affiliation":[{"name":"Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Huber-Lang","sequence":"additional","affiliation":[{"name":"Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelika","family":"Schnieke","sequence":"additional","affiliation":[{"name":"Chair of Livestock Biotechnology, School of Life Sciences Weihenstephan, Technische Universit\u00e4t M\u00fcnchen, 85354 Freising, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rolf E.","family":"Brenner","sequence":"additional","affiliation":[{"name":"Division for Biochemistry of Joint and Connective Tissue Diseases, Department of Orthopedics, University of Ulm, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1002\/jor.1100180517","article-title":"Effects of Harvest and Selected Cartilage Repair Procedures on the Physical and Biochemical Properties of Articular Cartilage in The Canine Knee","volume":"18","author":"Lee","year":"2000","journal-title":"J. Orthop. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1016\/S0140-6736(16)31658-0","article-title":"Nasal Chondrocyte-Based Engineered Autologous Cartilage Tissue For Repair Of Articular Cartilage Defects: An Observational First-In-Human Trial","volume":"388","author":"Mumme","year":"2016","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1016\/S0140-6736(16)31892-X","article-title":"Cartilage Repair Across Germ Layer Origins","volume":"388","author":"Rotter","year":"2016","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1089\/ten.teb.2013.0771","article-title":"Chondrogenic Differentiation of Mesenchymal Stem Cells: Challenges and Unfulfilled Expectations","volume":"20","author":"Somoza","year":"2014","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1097\/MOT.0000000000000463","article-title":"Xenotransplantation: Past, Present, and Future","volume":"22","author":"Ekser","year":"2017","journal-title":"Curr. Opin. Organ. Transplant."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1111\/xen.12034","article-title":"Discovery of the Natural Anti-Gal Antibody and its Past and Future Relevance to Medicine","volume":"20","author":"Galili","year":"2013","journal-title":"Xenotransplantation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/xen.12019","article-title":"Double Knockout Pigs Deficient in N-Glycolylneuraminic Acid and Galactose A-1,3-Galactose Reduce the Humoral Barrier to Xenotransplantation","volume":"20","author":"Lutz","year":"2013","journal-title":"Xenotransplantation"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1111\/xen.12142","article-title":"Potential Deleterious Role of Anti-Neu5Gc Antibodies in Xenotransplantation","volume":"22","author":"Salama","year":"2015","journal-title":"Xenotransplantation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"E12524","DOI":"10.1111\/xen.12524","article-title":"Generation of Cattle Knockout for Galactose-A1,3-Galactose and N-Glycolylneuraminic Acid Antigens","volume":"26","author":"Perota","year":"2019","journal-title":"Xenotransplantation"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1111\/xen.12176","article-title":"Early Graft Failure of Galtko Pig Organs in Baboons Is Reduced by Expression of a Human Complement Pathway-Regulatory Protein","volume":"22","author":"Azimzadeh","year":"2015","journal-title":"Xenotransplantation"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1084\/jem.160.5.1558","article-title":"Inhibition of Complement Activation on the Surface of Cells after Incorporation of Decay-Accelerating Factor (DAF) into Their Membranes","volume":"160","author":"Medof","year":"1984","journal-title":"J. Exp. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1084\/jem.166.5.1221","article-title":"The Mechanism of Action of Decay-Accelerating Factor (DAF). DAF Inhibits the Assembly of C3 Convertases by Dissociating C2a and Bb","volume":"166","author":"Fujita","year":"1987","journal-title":"J. Exp. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1084\/jem.175.6.1547","article-title":"Membrane Cofactor Protein (CD46) Protects Cells from Complement-Mediated Attack by an Intrinsic Mechanism","volume":"175","author":"Oglesby","year":"1992","journal-title":"J. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1113\/jphysiol.2001.013381","article-title":"CD59 Blocks Not Only the Insertion of C9 into MAC but Inhibits Ion Channel Formation by Homologous C5b-8 as well as C5b-9","volume":"539","author":"Farkas","year":"2002","journal-title":"J. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"29081","DOI":"10.1038\/srep29081","article-title":"Efficient Production of Multi-Modified Pigs for Xenotransplantation by \u2018Combineering\u2019, Gene Stacking and Gene Editing","volume":"6","author":"Fischer","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/S0891-5849(99)00223-3","article-title":"The Heme Synthesis and Degradation Pathways: Role in Oxidant Sensitivity","volume":"28","author":"Ryter","year":"2000","journal-title":"Free Radic. Biol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"L1029","DOI":"10.1152\/ajplung.2000.279.6.L1029","article-title":"Heme Oxygenase: Colors of Defense Against Cellular Stress","volume":"279","author":"Otterbein","year":"2000","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1089\/ars.2013.5674","article-title":"Signaling Function Of Heme Oxygenase Proteins","volume":"20","author":"Dennery","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.molmed.2008.12.004","article-title":"Heme Oxygenase-1: From Biology to Therapeutic Potential","volume":"15","author":"Soares","year":"2009","journal-title":"Trends Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.it.2009.05.007","article-title":"The Ubiquitin-Editing Enzyme A20 (TNFAIP3) Is a Central Regulator of Immunopathology","volume":"30","author":"Vereecke","year":"2009","journal-title":"Trends Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.tibs.2004.11.001","article-title":"A20 Inhibits NF-Kappab Activation by Dual Ubiquitin-Editing Functions","volume":"30","author":"Heyninck","year":"2005","journal-title":"Trends Biochem. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nrrheum.2010.196","article-title":"Role of Proinflammatory Cytokines in the Pathophysiology of Osteoarthritis","volume":"7","author":"Kapoor","year":"2011","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/S0014-4827(03)00180-0","article-title":"Induction of Matrix Metalloproteinase-13 Gene Expression by TNF-A is Mediated By MAP Kinases, AP-1, and NF-\u039ab Transcription Factors in Articular Chondrocytes","volume":"288","author":"Liacini","year":"2003","journal-title":"Exp. Cell Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"202","DOI":"10.22203\/eCM.v021a16","article-title":"Roles Of Inflammatory and Anabolic Cytokines in Cartilage Metabolism: Signals and Multiple Effectors Converge Upon MMP-13 Regulation in Osteoarthritis","volume":"21","author":"Goldring","year":"2011","journal-title":"Eur. Cells Mater."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Choi, M.-C., Jo, J., Park, J., Kang, H.K., and Park, Y. (2019). NF-\u039ab Signaling Pathways in Osteoarthritic Cartilage Destruction. Cells, 8.","DOI":"10.3390\/cells8070734"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"258","DOI":"10.22203\/eCM.v030a18","article-title":"Genetic Engineering Strategies to Prevent the Effects of Antibody and Complement on Xenogeneic Chondrocytes","volume":"30","author":"Sommaggio","year":"2015","journal-title":"Eur. Cells Mater."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1016\/j.joca.2013.09.002","article-title":"Inhibition of Complement Component C5 Protects Porcine Chondrocytes from Xenogeneic Rejection","volume":"21","author":"Sommaggio","year":"2013","journal-title":"Osteoarthr. Cartil."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1096\/fj.02-0630fje","article-title":"Delayed Rejection of Porcine Cartilage Is Averted by Transgenic Expression of Alpha1,2-Fucosyltransferase","volume":"17","author":"Costa","year":"2003","journal-title":"FASEB J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"150","DOI":"10.2119\/2007-00118.Joos","article-title":"IL-1beta Regulates FHL2 and Other Cytoskeleton-Related Genes in Human Chondrocytes","volume":"14","author":"Joos","year":"2008","journal-title":"Mol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6460","DOI":"10.4049\/jimmunol.172.10.6460","article-title":"Lack Of Galactose-Alpha-1,3-Galactose Expression on Porcine Endothelial Cells Prevents Complement-Induced Lysis but Not Direct Xenogeneic NK Cytotoxicity","volume":"172","author":"Baumann","year":"2004","journal-title":"J. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/s41419-019-1930-5","article-title":"Evidence of Necroptosis in Osteoarthritic Disease: Investigation of Blunt Mechanical Impact as Possible Trigger in Regulated Necrosis","volume":"10","author":"Riegger","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Riegger, J., Leucht, F., Palm, H.-G., Ignatius, A., and Brenner, R.E. (2019). Initial Harm Reduction by N-Acetylcysteine Alleviates Cartilage Degeneration after Blunt Single-Impact Cartilage Trauma In Vivo. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20122916"},{"key":"ref_33","first-page":"9061","article-title":"Effect Of Membrane-Bound Complement Regulatory Proteins on Tumor Cell Sensitivity to Complement-Dependent Cytolysis Triggered by Heterologous Expression of the A-Gal Xenoantigen","volume":"15","author":"Wang","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.joca.2020.01.004","article-title":"Crucial Role of the Terminal Complement Complex in Chondrocyte Death and Hypertrophy after Cartilage Trauma","volume":"28","author":"Riegger","year":"2020","journal-title":"Osteoarthr. Cartil."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s12026-011-8239-5","article-title":"Membrane Attack By Complement: The Assembly and Biology of Terminal Complement Complexes","volume":"51","author":"Tegla","year":"2011","journal-title":"Immunol. Res."},{"key":"ref_36","first-page":"381","article-title":"Biological, Biochemical and Biomechanical Characterisation of Articular Cartilage from the Porcine, Bovine and Ovine Hip and Knee","volume":"25","author":"Fermor","year":"2015","journal-title":"Biomed. Mater. Eng."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1046\/j.1469-7580.1998.19310023.x","article-title":"Collagen Fibre Arrangement in the Tibial Plateau Articular Cartilage of Man and Other Mammalian Species","volume":"193","author":"Gwynn","year":"1998","journal-title":"J. Anat."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s11427-013-4601-2","article-title":"Generation Of GGTA1 Biallelic Knockout Pigs via Zinc-Finger Nucleases and Somatic Cell Nuclear Transfer","volume":"57","author":"Bao","year":"2014","journal-title":"Sci. China Life Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1126\/science.1078942","article-title":"Production Of Alpha 1,3-Galactosyltransferase-Deficient Pigs","volume":"299","author":"Phelps","year":"2003","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/nbt0302-251","article-title":"Targeted Disruption of the Alpha1,3-Galactosyltransferase Gene in Cloned Pigs","volume":"20","author":"Dai","year":"2002","journal-title":"Nat. Biotechnol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1126\/science.1068228","article-title":"Production of Alpha-1,3-Galactosyltransferase Knockout Pigs by Nuclear Transfer Cloning","volume":"295","author":"Lai","year":"2002","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1096\/fasebj.13.13.1762","article-title":"Expression of the Human Alpha1,2-Fucosyltransferase in Transgenic Pigs Modifies the Cell Surface Carbohydrate Phenotype and Confers Resistance to Human Serum-Mediated Cytolysis","volume":"13","author":"Costa","year":"1999","journal-title":"FASEB J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.transproceed.2007.12.025","article-title":"Characterization of Cartilage from H-Transferase Transgenic Pigs","volume":"40","author":"Costa","year":"2008","journal-title":"Transplant. Proc."},{"key":"ref_44","first-page":"316","article-title":"Production of Transgenic Pigs Expressing Human Alpha 1,2-Fucosyltransferase to Avoid Humoral Xenograft Rejection","volume":"66","author":"Lipinski","year":"2010","journal-title":"Med. Weter."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1097\/00007890-199803270-00011","article-title":"Transgenic Expression of Human Alpha1,2-Fucosyltransferase (H-Transferase) Prolongs Mouse Heart Survival in an Ex Vivo Model of Xenograft Rejection","volume":"65","author":"Chen","year":"1998","journal-title":"Transplantation"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"E12560","DOI":"10.1111\/xen.12560","article-title":"Viable Pigs after Simultaneous Inactivation of Porcine MHC Class I and Three Xenoreactive Antigen Genes GGTA1, CMAH and B4GALNT2","volume":"27","author":"Fischer","year":"2020","journal-title":"Xenotransplantation"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1038\/nm.2543","article-title":"Identification Of A Central Role for Complement in Osteoarthritis","volume":"17","author":"Wang","year":"2011","journal-title":"Nat. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2580","DOI":"10.1016\/j.biocel.2013.08.018","article-title":"The NF-\u039ab Signalling Pathway in Osteoarthritis","volume":"45","author":"Rigoglou","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1111\/1440-1681.13291","article-title":"ABIN-1 Protects Chondrocytes from Lipopolysaccharide-Induced Inflammatory Injury through the Inactivation of NF-\u039ab Signalling","volume":"47","author":"Peng","year":"2020","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/S0002-9440(10)61682-3","article-title":"Interleukin-1 Induces Pro-Mineralizing Activity of Cartilage Tissue Transglutaminase and Factor Xiiia","volume":"159","author":"Johnson","year":"2001","journal-title":"Am. J. Pathol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.3727\/096368909X474249","article-title":"TNF, Pig CD86, and VCAM-1 Identified as Potential Targets for Intervention in Xenotransplantation of Pig Chondrocytes","volume":"18","author":"Sommaggio","year":"2009","journal-title":"Cell Transplant."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.4049\/jimmunol.1100433","article-title":"Multiple Receptors Trigger Human NK Cell-Mediated Cytotoxicity against Porcine Chondrocytes","volume":"188","author":"Sommaggio","year":"2012","journal-title":"J. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"E12549","DOI":"10.1111\/xen.12549","article-title":"Transgenic Expression Of Human CD47 Reduces Phagocytosis Of Porcine Endothelial Cells and Podocytes by Baboon and Human Macrophages","volume":"27","author":"Nomura","year":"2020","journal-title":"Xenotransplantation"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.1111\/ajt.12918","article-title":"Transgenic Expression of Human CD47 Markedly Increases Engraftment in a Murine Model of Pig-to-Human Hematopoietic Cell Transplantation","volume":"14","author":"Tena","year":"2014","journal-title":"Am. J. Transplant."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5070","DOI":"10.1111\/jcmm.15136","article-title":"Generating Low Immunogenic Pig Pancreatic Islet Cell Clusters for Xenotransplantation","volume":"24","author":"Valdivia","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"E86","DOI":"10.1097\/TP.0000000000001646","article-title":"Humoral Reactivity of Renal Transplant-Waitlisted Patients to Cells from GGTA1\/CMAH\/B4galnt2, and SLA Class I Knockout Pigs","volume":"101","author":"Martens","year":"2017","journal-title":"Transplantation"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1097\/TP.0000000000001924","article-title":"Swine Leukocyte Antigen Class II Is a Xenoantigen","volume":"102","author":"Ladowski","year":"2018","journal-title":"Transplantation"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.2337\/db11-1325","article-title":"Xenografted Islet Cell Clusters from INSLEA29Y Transgenic Pigs Rescue Diabetes and Prevent Immune Rejection in Humanized Mice","volume":"61","author":"Klymiuk","year":"2012","journal-title":"Diabetes"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3572","DOI":"10.1038\/s41598-017-03913-4","article-title":"LEA29Y Expression in Transgenic Neonatal Porcine Islet-Like Cluster Promotes Long-Lasting Xenograft Survival in Humanized Mice without Immunosuppressive Therapy","volume":"7","author":"Buerck","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e128616","DOI":"10.1172\/jci.insight.128616","article-title":"Dysregulated Integrin Av\u03b23 and CD47 Signaling Promotes Joint Inflammation, Cartilage Breakdown, and Progression of Osteoarthritis","volume":"4","author":"Wang","year":"2019","journal-title":"JCI Insight"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"E63","DOI":"10.2106\/JBJS.15.00573","article-title":"Cartilage-Repair Innovation at a Standstill: Methodologic and Regulatory Pathways to Breaking Free","volume":"98","author":"Lyman","year":"2016","journal-title":"J. Bone Jt. Surg. Am."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/8\/2152\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:48:27Z","timestamp":1760165307000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/8\/2152"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,20]]},"references-count":61,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["cells10082152"],"URL":"https:\/\/doi.org\/10.3390\/cells10082152","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2021,8,20]]}}}