title: Xenogeneic transplantation of articular chondrocytes into full-thickness articular cartilage defects in minipigs: fate of cells and the role of macrophages.
abstract: Xenogeneic or allogeneic chondrocytes hold great potential to build up new cartilage in vivo. However, immune rejection is a major concern for the utility of universal donor-derived cells. In order to verify the reported immune privilege of chondrocytes in vivo, the aim of this study was to assess engraftment of human articular chondrocytes (HAC) in minipig knee cartilage defects and their contribution to cartilage regeneration. HAC were transplanted matrix-assisted within two hydrogels into full-thickness cartilage defects of minipigs or implanted ectopically into immune deficient mice to assess redifferentiation capacity. At 2 and 4 weeks after surgery, cell-persistence and host cell invasion were monitored by species-specific in situ hybridization and RT-PCR. Early tissue regeneration was evaluated by histomorphometry and a modified O'Driscoll score. HAC capable of successful in vivo chondrogenic redifferentiation persisted at ectopic sites for 4 weeks in both carrier materials. Early defect regeneration involved extensive host cell invasion and a decline of HAC to less than 5 % of initial cell numbers in 6/12 defects within 2 weeks. Few clusters of persisting HAC within collagen type II-rich tissue were surrounded by porcine macrophages. Four weeks after cell transplantation, most of the defects contained well-integrated cell-rich tissue free of human cells with no apparent difference between hydrogel carriers. In summary, HAC failed to engraft in porcine articular cartilage defects despite their ability for successful in vivo redifferentiation. The co-localization of macrophages to hydrogel-implanted HAC suggests active graft rejection without evidence for an immune-privileged status of xenogeneic chondrocytes in a large animal joint.
authors.affiliation: Research Center for Experimental Orthopaedics, Orthopaedic University Hospital Heidelberg, Schlierbacher Landstrasse 200a, 69118, Heidelberg, Germany, thomas.niemietz@med.uni-heidelberg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Niemietz
authors.forename: Gesa
authors.initials: G
authors.lastname: Zass
authors.forename: Sébastien
authors.initials: S
authors.lastname: Hagmann
authors.forename: Solvig
authors.initials: S
authors.lastname: Diederichs
authors.forename: Tobias
authors.initials: T
authors.lastname: Gotterbarm
authors.forename: Wiltrud
authors.initials: W
authors.lastname: Richter
mesh_terms: D000818:Animals; D016723:Bone Remodeling; D002358:Cartilage, Articular / Q000473:pathology*; D002454:Cell Differentiation; D002470:Cell Survival; D019902:Chondrocytes / Q000166:cytology / Q000637:transplantation*; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D016513:Mice, SCID; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D013045:Species Specificity; D013552:Swine; D013556:Swine, Miniature; D014183:Transplantation, Heterologous
chemical_list: D024043:Collagen Type II; D012333:RNA, Messenger; D007041:Hypoxanthine Phosphoribosyltransferase