Focal damage to cartilage sustained in serious joint injuries typically goes unrepaired and may progress to post-traumatic osteoarthritis. However, in a bovine explant model we found that cartilage damage provoked the emergence of highly migratory cells that homed to the site of injury and appeared to re-populate dead zones. We hypothesized that the migrating population were chondrogenic progenitor cells engaged in cartilage repair. The surfaces of bovine osteochondral explants injured by blunt impact were serially imaged to follow cell migration. Migrating cells harvested from cartilage surfaces were tested for clonogenic, side population, chemotactic activities and multipotency in in vitro assays. Gene expression in migrating cells was evaluated by microarray and their potential for spontaneous cartilage regeneration was assessed in a chondral defect model. Migrating cells emerged from superficial zone cartilage and efficiently repopulated areas where chondrocyte death had occurred. In confocal examination with high magnification, we could clearly observe the morphology of elongated progenitor cells which were migrating toward cartilage defect area and these cells were distinguishable from round chondrocytes. The cells were also activated to migrate in cartilage defect model. Most migrated cells in fibrin were morphologically elongated and a few cells were differentiating to chondrocyte-like cells with the deposit of proteoglycans. These cells proved to be highly clonogenic and capable of chondrogenesis and osteogenesis, but not adipogenesis. They were more active in chemotaxis assays than chondrocytes, showed a significantly larger side population, and over-expressed progenitor cell markers and genes involved in migration, chemotaxis, and proliferation. To active migration of chondrogenic progenitor cells (CPCs) short-term enzymatic method was used around edge of cartilage defect. Surprisingly, CPCs migrated into fibrin defect and were differentiating into chondrocytes with abundant deposit of proteoglycans. This result strongly supports that progenitor cells are activated in traumatic cartilage injury and have great potential for cartilage repair. In conclusion, migrating cells on injured explant surfaces are chondrogenic progenitors from the superficial zone that were activated by cartilage damage to attempt repair. Facilitating this endogenous process could allow repair of focal defects that would otherwise progress to post-traumatic osteoarthritis.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23085号 / 医博第4712号 / 新制||医||1049(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 安達 泰治, 教授 戸口田 淳也, 教授 別所 和久 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM