We previously compared mesenchymal stem cells (MSCs) from a variety of mesenchymal tissues and demonstrated that synovium-MSCs had the best expansion and chondrogenic ability in vitro in humans and rats. In this study, we compared the in vivo chondrogenic potential of rabbit MSCs. We also examined other parameters to clarify suitable conditions for in vitro and in vivo cartilage formation. MSCs were isolated from bone marrow, synovium, adipose tissue, and muscle of adult rabbits. Proliferation potential and in vitro chondrogenic potential were compared. Toxicity of the tracer DiI for in vitro chondrogenesis was also examined. MSCs from each tissue were embedded in collagen gel and transplanted into full thickness cartilage defects of rabbits. Cartilage matrix production was compared histologically. The effects of cell density and periosteal patch on the in vivo chondrogenic potential of synovium-MSCs were also examined. Synovium- and muscle-MSCs had a higher proliferation potential than other cells. Pellets from synovium- and bone-marrow-MSCs showed abundant cartilage matrix. DiI had no significant influence on in vitro cartilage formation. After transplantation into cartilage defects, synovium- and bone-marrow-MSCs produced much more cartilage matrix than other cells. When synovium-MSCs were transplanted at a higher cell density and with a periosteal patch, more abundant cartilage matrix was observed. Thus, synovium- and bone-marrow-MSCs had greater in vivo chondrogenic potential than adipose- and muscle-MSCs, but synovium-MSCs had the advantage of a greater proliferation potential. Higher cell density and a periosteum patch were needed to obtain a high production of cartilage matrix by synovium-MSCs.

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We previously demonstrated that synovium-derived MSCs had greater in vitro chondrogenic ability than other mesenchymal tissues, suggesting a superior cell source for cartilage regeneration. Here, we transplanted undifferentiated synovium-derived MSCs into a full-thickness articular cartilage defect of adult rabbits and defined the cellular events to elucidate the mechanisms that govern multilineage differentiation of MSCs. Full-thickness osteochondral defects were created in the knee; the defects were filled with 1,1-dioctadecyl-3,3,3,3-tetramethylindocarbocyanine perchlorate-labeled MSCs and covered with periosteum. After 4 weeks, although the cell density decreased, transplanted MSCs produced a great amount of cartilage matrix extensively. The periosteum became thinner, and chondroprogenitors in the periosteum produced a small amount of cartilage matrix. In the deeper zone, transplanted MSCs progressed to the hypertrophic chondrocyte-like cells. In the deep zone, some transplanted cells differentiated into bone cells and were replaced with host cells thereafter. In the next phase, the border between bone and cartilage moved upwards. In addition, integrations between native cartilage and regenerated tissue were improved. Chondrocyte-like cells derived from the transplanted MSCs still remained at least after 24 weeks. Histological scores of the MSC group improved continuously and were always better than those of two other control groups. Immunohistological analyses and transmission electron microscopy confirmed that the MSCs produced abundant cartilage matrix. We demonstrated that transplanted synovium-derived MSCs were altered over a time course according to the microenvironments. Our results will advance MSC-based therapeutic strategies for cartilage injury and provide the clues for the mechanisms that govern multilineage differentiation of MSCs. STEM CELLS 2007;25:689 -696

Objective. Synovial mesenchymal stem cells (MSCs) are an attractive cell source for cartilage regeneration because of their high chondrogenic ability. In this study, we examined the synovium of patients with medial compartment knee osteoarthritis (OA) to determine the proportion of MSCs in relation to cellular compartmentalization, and to identify the culture parameters that could affect the chondrogenic potential of synovial MSCs.Methods. Human synovium was collected from 4 different harvest sites in the knees of patients with medial compartment OA. Each synovial tissue sample was divided into 2 parts, one for histologic assessment and the other for analysis of the cell size, surface epitopes, and chondrogenic potential of colony-forming cells in vitro.Results. The numbers of ␣-smooth muscle actinpositive vessels and CD31؉ endothelial cells were higher in the medial outer region than in the other regions of OA synovial tissue. The numbers of these cells correlated with the number of colony-forming cells.In parallel with increasing duration of the preculture period, the size of the cells increased, while the chondrogenic potential decreased, and this was correlated with expression of CD90.Conclusion. Medial compartment knee OA demonstrates variability in the distribution of vessels, which results in a varying distribution of MSCs. The preculture period should be utilized to assess both the potential for expansion and the chondrogenic potential of MSCs.

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