Intra-Articular Injection of Human Synovial Membrane-Derived Mesenchymal Stem Cells in Murine Collagen-Induced Arthritis: Assessment of Immunomodulatory Capacity In Vivo

Abstract

The aim of this study was to evaluate the efficacy of human synovial membrane-derived MSCs (SM-MSCs) in murine collagen-induced arthritis (CIA). Male mice (age 7–9 weeks) were injected intra-articularly with SM-MSCs obtained from patients with osteoarthritis, on days 28, 32, and 38 after bovine type II collagen immunization. The efficacy of SM-MSCs in CIA was evaluated clinically and histologically. Cytokine profile analyses were performed by real-time polymerase chain reaction and multiplex analyses. Splenic helper T (Th) cell and regulatory B cell subsets were analyzed by flow cytometry. Intra-articular SM-MSC injection ameliorated the clinical and histological severity of arthritis. Decrease in tumor necrosis factor-α, interferon-γ, and interleukin- (IL-) 17A and increase in IL-10 production were observed after SM-MSC treatment. Flow cytometry showed that Th1 and Th17 cells decreased, whereas Th2, regulatory T (Treg), and PD-1+CXCR5+FoxP3+ follicular Treg cells increased in the spleens of SM-MSC-treated mice. Regulatory B cell analysis showed that CD21hiCD23hi transitional 2 cells, CD23lowCD21hi marginal zone cells, and CD19+CD5+CD1d+IL-10+ regulatory B cells increased following SM-MSC treatment. Our results demonstrated that SM-MSCs injected in inflamed joints in CIA had a therapeutic effect and could prevent arthritis development and suppress immune responses via immunoregulatory cell expansion.

Synovia-Derived Mesenchymal Stem Cell Application in Musculoskeletal Injuries: A Review

“…The unique matrix structure, rich in collagen fibers, proteoglycans, and interstitial fiber, provides a viscoelastic environment that allows the AC to support its biomechanical functions [8]. It has been well established that the AC has limited self-healing capacities [3][4][5][7][8][9][10][11][12][13][14][15] due to its intrinsic characteristics, namely its avascular nature, limited number of resident stem cells, and unique matrix organization [4]. Partial defects on mature cartilage do not heal spontaneously.…”

“…This procedure promotes a shortterm relief on patient's symptoms but fails to repair the damaged tissue and hyaline cartilage [4]. RA is a systemic autoimmune disease, characterized by a continuous inflammation phenomenon, a result of an intrinsic imbalance, culminating in a major synovial hyperplasia, bone, and cartilage damage [15]. Treatments involving artificial prosthesis are quite invasive and lifetime limited [9], as well as the mosaicplasty treatment technique is invasive and causes damages to the donor site [13] and fails to restore functional, as well as, phenotypically stable hyaline cartilage [4].…”

“…Regenerative medicine approaches regarding stem cell therapies have been developed in the past decades as a promising strategy, focusing primarily on immune/anti-inflammatory modulation [15] and cancer treatment [29]. Furthermore, their potential has been employed in cartilage [30] and skeletal muscle repair [1], the latter in a more immature state of development.…”

“…It can be obtained arthroscopically, with a minor degree of invasiveness [10] through a small biopsy [31] and with minor complications at the donor site [12]. It is a quite accessible source, as the SM is routinely removed from OA patients for knee replacement or other arthroscopic interventions [15]. It can be cryopreserved and stored for future use, as it is not negatively influenced by cryopreservation methods [31].…”

“…Recently, SM-MSCs from OA individuals have been reported to suppress T-cell proliferation and to suppress T-reg populations in vitro, when cocultured with allogenic lymphocytes. Thus, indicating their ability to suppress the immune response and prevent OA development [15,35]. Yan et al reported SM-MSCs' ability to prevent autoimmune disease and recover self-tolerance after repeated IA administrations of SM-MSCs from OA individuals to a collagen-induced arthritis murine model.…”