We investigated the effects of single or repetitive intra-articular injections of synovial mesenchymal stem cells (MSCs) on a rat osteoarthritis (OA) model, and elucidated the behaviors and underlying mechanisms of the stem cells after the injection. One week after the transection of the anterior cruciate ligament (ACL) of wild type Lewis rats, one million synovial MSCs were injected into the knee joint every week. Cartilage degeneration was evaluated with safranin-o staining after the first injection. To analyze cell kinetics or MSC properties, luciferase, LacZ, and GFP expressing synovial MSCs were used. To confirm the role of MSCs, species-specific microarray and PCR analyses were performed using human synovial MSCs. Histological analysis for femoral and tibial cartilage showed that a single injection was ineffective but weekly injections had significant chondroprotective effects for 12 weeks. Histological and flow-cytometric analyses of LacZ and GFP expressing synovial MSCs revealed that injected MSCs migrated mainly into the synovium and most of them retained their undifferentiated MSC properties though the migrated cells rapidly decreased. In vivo imaging analysis revealed that MSCs maintained in knees while weekly injection. Species-specific microarray and PCR analyses showed that the human mRNAs on day 1 for 21 genes increased over 50-fold, and increased the expressions of PRG-4, BMP-2, and BMP-6 genes encoding chondroprotective proteins, and TSG-6 encoding an anti-inflammatory one. Not single but periodic injections of synovial MSCs maintained viable cells without losing their MSC properties in knees and inhibited osteoarthritis (OA) progression by secretion of trophic factors.

The induction of synovial tissue to the meniscal lesion is crucial for meniscal healing. Synovial Mesenchymal stem cells (MSCs) are an attractive cell source because of their high proliferative and chondrogenic potentials. We examined whether transplantation of synovial MSCs promoted healing after meniscal repair of extended longitudinal tear of avascular area in a microminipig model. Longitudinal tear lesion was made in medial menisci and sutured in both knees, and then a synovial MSC suspension was administered for 10 min only in unilateral knee. The sutured meniscus was evaluated morphologically and biomechanically at 2, 4, and 12 weeks. The behavior of transplanted MSCs was also examined. The meniscal healing at 12 weeks was significantly better in the MSC group than in the control group; macroscopically, histologically and by T1rho mapping analysis. Transmission electron microscopic analysis demonstrated that the meniscus lesion was occupied by dense collagen fibrils only in the MSC group. Biomechanical analysis revealed that the tensile strength to failure of the meniscus higher in the MSC group than in the control group in each microminipig. Synovial tissue covered better along the superficial layer from the outer zone into the lesion of the meniscus in the MSC group at 2 and 4 weeks in each microminipig. Synovial MSCs labeled with ferucarbotran were detected in the meniscus lesion and adjacent synovium by MRI at 2 weeks. Transplantation of synovial MSCs promoted healing after meniscal repair with induction of synovium into the longitudinal tear in the avascular zone of meniscus in pigs.

Osteoarthritis (OA), a common chronic joint disorder in both humans and canines, is characterized by a progressive loss of articular cartilage. Canines can serve as an animal model of OA for human medicine, and this research can simultaneously establish effective veterinary treatments for canine OA. One attractive treatment that can lead to cartilage regeneration is the use of mesenchymal stem cells (MSCs). However, for canine OA, little information is available regarding the best source of MSCs. The purpose of this study was to identify a promising MSC source for canine cartilage regeneration. We collected synovial, infrapatellar fat pad, inguinal adipose, and bone marrow tissues from six canines and then conducted a donor-matched comparison of the properties of MSCs derived from these four tissues. We examined the surface epitope expression, proliferation capacity, and trilineage differentiation potential of all four populations. Adherent cells derived from all four tissue sources exhibited positivity for CD90 and CD44 and negativity for CD45 and CD11b. The positive rate for CD90 was higher for synovium-derived than for adipose-derived and bone marrow-derived MSCs. Synovium-derived and infrapatellar fat pad-derived MSCs displayed substantial proliferation ability, and all four populations underwent trilineage differentiation. During chondrogenesis, the wet weight was heavier for cartilage pellets derived from synovium MSCs than from the other three sources. The synovium is therefore a promising source for MSCs for canine cartilage regeneration. Our findings provide useful information about canine MSCs that may be applicable to regenerative medicine for treatment of OA.

Based on evidence from several other tissues, cartilage stem/progenitor cells in the auricular cartilage presumably contribute to tissue development or homeostasis of the auricle. However, no definitive studies have identified or characterized a stem/progenitor population in mice auricle. The 5-bromo-2′-deoxyuridine (BrdU) label-retaining technique was used to label dividing cells in fetal mice. Observations one year following the labeling revealed that label-retaining cells (LRCs) were present specifically in auricular perichondrium at a rate of 0.08±0.06%, but LRCs were not present in chondrium. Furthermore, LRCs were successfully isolated and cultivated from auricular cartilage. Immunocytochemical analyses showed that LRCs express CD44 and integrin-α₅. These LRCs, putative stem/progenitor cells, possess clonogenicity and chondrogenic capability in vitro. We have identified a population of putative cartilage stem/progenitor cells in the auricular perichondrium of mice. Further characterization and utilization of the cell population should improve our understanding of basic cartilage biology and lead to advances in cartilage tissue engineering and novel therapeutic strategies for patients with craniofacial defects, including long-term tissue restoration.

Meniscus surgery is the most commonly performed orthopedic surgery, and despite recent emphasis on saving the meniscus, the current status of meniscus surgeries is little known in many countries, including Japan. The National Database of Health Insurance Claims and Specific Health Checkups of Japan and the Statistics of Medical Care Activities in Public Health Insurance track meniscus surgeries through health insurance claims. The National Database provides the numbers for 2014 and 2015, and the Statistics of Medical Care Activities provides the numbers from June 2011 to June 2016. Our aim was to analyze isolated meniscus surgery numbers and meniscus repair ratios by age group based on the National Database and evaluate trends of meniscus repair ratios for the latest six years from the Statistics of Medical Care Activities. Meniscus surgeries by age group were counted from the National Database for 2014-2015, and meniscus repair ratios (meniscus repairs/meniscus surgeries) were calculated. The numbers were also counted from the Statistics of Medical Care Activities in 2011-2016. For statistical analysis of annual trends of meniscus repair ratios, the Cochran-Armitage trend test was used. Meniscus surgeries with concomitant knee ligament surgeries were excluded. According to the National Database, isolated meniscus surgeries totaled 34,966 in 2015, with peak ages of patients in their late teens and 60s. The meniscus repair ratio was 19% in 2014 and 24% in 2015. According to the Statistics of Medical Care Activities, the meniscus repair ratio was 9% in 2011 and significantly increased to 25% in 2016 (p = 0.0008). The ratio also increased significantly in each age group between the early 20s and late 70s. Approximately 35,000 meniscus surgeries are performed in Japan annually, with peak ages in the late teens and 60s. The number of meniscus repairs has increased over the past six years.