【Objectives】 Mesenchymal stem cells (MSC) possess immunoregulatory ability with osteoblastogenesis which makes them an ideal tool for arthritis treatment. Here we utilized nano-fiber poly-lactic-co-glycolic acid as a scaffold to deliver MSC into arthritic models. 【Methods】 MSC were injected intra-articularly (IA) or intra-peritoneally (IP) or seeded on nano-fiber and implanted into ankles (nano-MSC) of collagen induced arthritis (CIA) rats. 【Results】 Arthritis and bone destruction were significantly suppressed by nano-MSC treatment, while IA or IP demonstrated no effects. Serum anti-type II collagen IgG and the proliferation and cytokine production of CD4+ T cells in nano-MSC rats were significantly decreased compared to control rats. Inoculation of MSC transfected with green fluorescent protein plasmid DNA showed MSC remained within nano-fiber and did not migrate to other organs. MSC cultured on nano-fiber showed increased transforming growth factor (TGF)-β1 production compared to MSC cultured on plate. 【Conclusion】 Administration of MSC with nano-fiber efficiently suppressed arthritis, bone destruction, suggesting a novel MSC delivery system for future arthritis treatment.

関節リウマチは進行性関節破壊を必発するが，破壊された関節機能は不可逆的で，修復を目指した治療の開発が必須である．我々は，多分化能を有するヒト骨髄由来間葉系幹細胞（MSC）の炎症性関節炎への治療応用を目指してきた．まず，ヒトMSCはIL-1等の炎症性サイトカインの存在下でも骨芽細胞，骨細胞への分化が強力に誘導された．その過程には，Wnt5a/ROR2の誘導およびその下流のシグナル経路の関与が示された．脂肪組織由来間葉系幹細胞もIL-6刺激で骨芽細胞様の分化を呈した．また，IL-1で刺激したMSCはRANKLよりOPG産生が優位で，破骨細胞の分化抑制を介して関節破壊を制御した．一方，MSCから軟骨細胞への分化は，IL-6/Stat3リン酸化を介して誘導され，IL-17/Sox9リン酸化制御を介して抑制され，異なる刺激調節系の存在が示された．さらに，ナノファイバーシートに播種したヒトMSCをラット関節近傍に移植すると，関節炎，骨破壊が臨床的，構造的，病理学的に抑制された．ナノファイバー播種MSC治療群では関節局所のIL-1やIL-6発現や所属リンパ節腫大，脾腫，血清II型コラーゲン抗体産生が抑制され，リンパ節のT細胞の増殖，サイトカイン産生が阻害され，局所の治療効果と全身性免疫応答の抑制作用を有した．さらに，GFPで標識したMSCは移植部に留まり，局所で産生されるTGF-等の産生を介して免疫応答が抑制された．以上，ナノファイバーに播種したヒトMSCは，骨芽細胞や軟骨細胞への分化，破骨細胞の分化制御，全身性免疫応答の抑制作用を有し，炎症性関節炎の疾患制御，関節機能の再生・修復を目指す上で有効なツールである事が示された．

Mesenchymal stem cells (MSCs) possess immunoregulatory ability with multipotency which makes this cells an ideal tool for treatment of rheumatoid arthritis (RA). Aiming clinical use, the effect of MSCs combined with nano-fiber poly-lactic-co-glycollic acid sheet scaffold (nano-sheet) was assessed. MSCs were injected intra-articularly (IA) or intra-peritoneally (IP) or seeded on nano-sheet and implanted into ankles (IMP) of collagen induced arthritis (CIA) rats. IA or IP treatment demonstrated no effects whereas, IMP significantly suppressed arthritis evaluated by arthritis score and body weight. X-ray, micro-CT and histological analysis revealed markedly suppressed joint destruction with IMP but not with IA or IP. Furthermore, draining lymph nodes were decreased in size and IL-1β expression, serum anti-type II collagen IgG and proliferation of T cell ex vivo was significantly suppressed. Culture of MSCs on Nano-sheet in vitro increased TGF-β1 production while IL-6 was decreased compared to MSCs cultured on plate. Local delivery of MSCs with nano-sheet scaffold efficiently suppressed immune response in CIA. These data suggest the efficacy of nano-sheet with MSCs for RA.

Objectives: Mesenchymal stem cells (MSCs) are considered as a possible tool for treatment of rheumatoid arthritis (RA) due to their immunoregulatory ability and pluripotency. Here we established an effective delivery system of MSCs on a arthritis animal model. Methods: MSCs were seeded on poly-lactic-co-glycollic acid (PLGA) scaffold then implanted into ankles (IMP) of collagen induced arthritis (CIA) rats or simply injected intra-articularly (IA) or intra-peritoneally (IP). Results: IMP to bilateral ankles significantly suppressed the severity of arthritis evaluated by arthritis score, hind paw thickness and body weight compared to CIA, while IA and IP showed less or no effect. Accordingly, bone destruction detected by X-ray, micro CT and infiltration of inflammatory cells, damage of cartilage and bone destruction detected histologically were reduced in IMP group but not in other groups. Furthermore, the size of the draining lymph nodes was smaller with reduced germinal center formation in the IMP group. Conclusion: Implantation of MSCs with nano-fiber scaffold efficiently suppressed arthritis and bone destruction, suggesting a novel MSCs delivery system for future RA treatment.