**2. Mesenchymal stem cells in RA synovial tissue**

#### **2.1. Multipotency**

MSCs are self-renewing, multipotent progenitor cells with multilineage potential to differentiate into various types of cells including chondrocytes, osteoblasts, and adipocytes [9–15]. While MSCs are most commonly isolated from bone marrow [13] and proliferate rapidly in vitro, they are also isolated from other tissues including adipose tissue [16], placenta [17], and umbilical cord blood [18]. Due to their accessibility and convenient expansion protocols, ethical dilemmas and risk of tumor formation, such as in ES cells and iPS cells, can also be avoided and therefore MSCs are easy to use in clinical application and have been recognized as promising candidates for cell therapy.

We investigated earlier the potential of chondrogenic differentiation of MSCs derived from bone marrow and synovial fluid in human osteoarthritis (OA) [19, 20]. Our study concluded that both bone marrow MSCs (BMMSCs) and synovial fluid MSCs (SFMSCs) had a potential of cell proliferation and chondrogenic differentiation. Both cells were fibroblast-like cells and had similar cell surface antigen in flow cytometry analysis, namely positive for CD13, CD44, and CD105 and negative for CD10, CD14, and CD45. However, aggrecan (AGG) mRNA expression in SFMSCs, which are traditionally associated with chondrogenic commitment, was a significant high compared to BMMSCs in vitro. According to other researches, SFMSCs are considered the same as synovial MSCs [21, 22]. Study of Sekiya et al. [23] reported that synovial MSCs are a candidate cell source for regenerative medicine of cartilage due to their high chondrogenic ability. They demonstrated that chondrogenic potentials of synovial MSCs between RA and OA patients were similar, as the weight of the pellet is a quantitative indicator of the ability of MSCs to produce chondrogenesis in vitro. Therefore, autologous synovial MSCs can be expected in cartilage regeneration for RA patients. According to previous reports [24], there was a negative relationship between chondrogenic potential of synovial MSCs and magnitude of synovitis in RA, and some properties of synovial MSCs vary dependent on the diseases patients have. Also, it was reported that chondrogenic potential in RA patients was inferior to that in OA patients. However, Jones et al. [24] reported that effective suppression of joint inflammation is necessary for the development of autologous MSC treatments aimed at cartilage regeneration in RA and synovial MSCs can be expected for RA patients with the inflammation well controlled as well as OA patients.

#### **2.2. Immunosuppresive effect**

Previous reports have suggested that synovial MSCs harvested from RA were capable of immunosuppression in vitro [24]. However, other reports have suggested that the immunomodulatory function of synovial MSCs seems to be disturbed and causes an inefficacy due to various factors within RA microenvironment and as a result of a direct contact with inflammatory cells and cytokines [25]. In RA synovial tissue, synovial MSCs appear to play an important role in controlling the inflammation and immune hemostasis.
