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POS0412 ENHANCING SURVIVAL AND THERAPEUTIC EFFECT OF MESENCHYMAL STEM CELLS IN RAT MODEL OF RHEUMATOID ARTHRITIS VIA NANOMODIFICATION

Mesenchymal stem cells (MSCs) have immunomodulatory, multilineage differentiation, and inflammatory/injury site-homing properties. These unique therapeutic features enable MSCs to be used in the treatment of rheumatoid arthritis (RA). However, MSCs therapy is still facing multiple obstacles in RA. First, MSCs are sensitive to inflammatory microenvironment (e.g., high level of reactive oxygen species [ROS]) and hence lose viability and immune regulatory effect when exposed in the inflamed joint. Second, uncontrolled differentiation of MSCs leads to the failure of cartilage repair.The aim of this study was to develop nanoparticle (NP)-modified MSCs that can maintain their biofunctions under the RA-associated oxidized stress and chondrogenically differentiate to repair cartilage.Copper sulfide@manganese dioxide (CuS@MnO2) NPs were sythesized, then modified with an MSC-targeting peptide (VTAMEPGQ, termed VQ) and loaded with metformin (MET) to produce VQ-CuS@MnO2/MET (termed VCMM) NPs. After cellular uptake, the NP-modified VCMM-MSCs were obtained. The basic functions, chondrogenesis, anti-inflammatory effect and cell viability under oxidized stress of VCMM-MSCs were studied in vitro. Further, VCMM-MSCs were intravenously (i.v.) injected into rat models of collegan-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) to evaluate their survival and therapeutic effect in vivo.The NP-modified VCMM-MSCs exhibited stronger capabilities of cell migration and chondrogenesis relative to bare MSCs. VCMM-MSCs were also better than bare MSCs in terms of anti-inflammation towards lipopolysaccharide-induced M1 macrophages (RAW264.7). Moreover, VCMM-MSCs could survive under the RA-associated oxidized stress through catalyzing intracelluar ROS into oxygen by the superoxide dismutase (SOD)- and catalase (CAT)-like activities of the NPs, whereas approximately half of bare MSCs were dead. After i.v. injection into CIA and AIA rats, VCMM-MSCs lived longer and accumulated more abundant in the inflamed joints relative to bare MSCs (determined by in vivo fluorescence imaging). They promoted the repolarization of macrophages from M1 to M2 type in synovium, thereby inhibiting synovial inflammation in vivo. Further, VCMM-MSCs enhanced the sythesis of glycosaminoglycan and type II collegan in cartilage and thus promoted joint reapir.The NP-modified VCMM-MSCs alleviated arthritis syndrome of both CIA and AIA models through reducing synovial hyperplasia and cartilage destruction. Nanomodification of MSCs may provide a new strategy to improve stem cell therapy in RA and other inflammatory diseases.This study was supported by National Natural Science Foundation of China (81902198).None declared.