**1. Introduction**

Rheumatoid arthritis (RA) is a refractory systemic autoimmune disease with chronic synovial inflammation. Sustained synovial inflammation leads to progressive destruction of bone and cartilage. In the pathogenesis of RA, activated T cells and antigen-presenting cells such as monocytes and macrophages produce inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-2, IL-6, and interferon-γ (INF-γ). They promote release of inflammatory mediators, infiltration of inflammatory cells, production

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

of autoantibody, proliferation of the synovial cells, and activation of the osteoclasts, resulting in the bone and the cartilage destruction [1–3].

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

Efficacy of SSEA-3 Positive Cells Derived from Synovial Tissue in Rheumatoid Arthritis

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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.

**3. Stage-specific embryonic antigen-3 (SSEA-3) positive cells in RA** 

Multilineage differentiating stress enduring (Muse) cells are a novel type of pluripotent stem cells and recently reported as adult human MSCs without introducing exogenous genes. They are present in various organs such as pancreas, dermis, umbilical cord, fat, liver, trachea, bone marrow, spleen [26–31] and are contained at a proportion of several percent in cultured mesenchymal stem cells [26], 4–9% in human adipose tissue [27] and 1–2% in human skin fibroblasts [26]. Muse cells are able to differentiate into cells from all three embryonic germ layers both spontaneously and under media-specific induction. Also, Muse cells have a low tumor-forming ability compared with embryonic stem (ES) cells and a high efficiency of change to iPS cells by Yamanaka gene introduction [32]. They can migrate to damaged tissues by intravenous injection in vivo, spontaneously differentiate into cells compatible with the targeted tissue, and contribute to tissue repair. Thus, Muse cells will be expected to play an important role in regenerative therapy by further studies. SSEA-3 is a marker of human embryonic stem cell. Muse cells are able to be isolated as SSEA-3 positive cells from cultured

SSEA-3 positive cells are autologous cells and act as stem cells in the blood and also possess immunosuppression effects [28–31]. Therefore, they could be one of novel cell sources as cell therapy in RA. We studied the possibility of SSEA-3 positive cells derived from RA synovial tissue.

We used synovial tissue harvested from 13 RA patients at the time of joint surgery in our hospital (**Table 1**) [33]. Diagnosis of RA for all patients was based on the American College of Rheumatology (ACR) criteria in 1987 [34] or the ACR/European League Against Rheumatism

inflammation well controlled as well as OA patients.

**2.2. Immunosuppresive effect**

**synovial tissue**

mesenchymal cells.

**3.2. SSEA-3 as cell therapy in RA**

*3.2.1. SSEA-3 positive cells in RA synovial tissue*

**3.1. SSEA-3**

In the last few years, development of disease-modifying antirheumatic drugs (DMARDs) and biological agents targeting inflammatory cytokines has been major advances in the treatment of RA. Biological agents targeting inflammatory cytokines such as TNF-α, which has been shown to be a key factor in the pathology of RA, are effective for RA. These are known to improve disease activity and inhibit the progress of joint destruction. The best possible treatment goal for patients is clinical remission and consistently stopping continuing joint damage through erosions.

However, treatment to restore joints that have been destroyed irreversibly is not to be established yet. Also, DMARDs or biological agents can have serious side effects affecting the blood, liver, or kidneys rarely. Therefore, a novel RA treatment that enables restoration of destroyed joints is needed. Use of mesenchymal stem cells (MSCs) derived from bone marrow as a biological method for repairing articular cartilage defects have been investigated [4–8]. We think that the treatment by thus autologous cells can overcome these problems.
