Abstract
BackgroundRheumatoid arthritis (RA) is a debilitating and painful disease leading to increased morbidity and mortality and novel therapeutic approaches are needed. The purpose of this study was to elucidate if mesenchymal stem cells (MSCs) injected in the joints of mice with arthritis are therapeutic, reducing joint swelling and cartilage destruction.MethodsMurine mesenchymal stem cells (mMSCs) were isolated from bone marrow of C57Bl/6 mice and expanded in culture. Cells were tested for immunophenotype and their ability to form colonies and to differentiate into chondrocytes, osteocytes and adipocytes. Antigen-induced arthritis (AIA) was induced by intra-articular injection of methylated bovine serum albumin into the knee joints of preimmunized C57Bl/6 mice. After one day, when peak swelling occurs, 500,000 mMSCs labelled with red fluorescent cell tracker CM-DiI were injected intra-articularly in the right knee joint. Left knee joints were treated as controls by receiving PBS injections. Differences between groups were calculated by Mann Whitney U test or unpaired t tests using GraphPad Prism software version 5.ResultsKnee joint diameter (swelling) was measured as a clinical indication of joint inflammation and this parameter was significantly less in MSC-treated mice compared to control-treated animals 48 hours after arthritis induction. This difference continued for ~7 days. CM-DiI-labelled MSCs were clearly visualised in the lining and sublining layers of synovium, in the region of the patella and femoral and tibial surfaces. By day 3, parameters indicative of disease severity, including cartilage depletion, inflammatory exudate and arthritic index were shown to be significantly reduced in MSC-treated animals. This difference continued for 7 days and was further confirmed by histological analysis. The serum concentration of tumour necrosis factor α was significantly decreased following MSC administration.ConclusionsOur results reveal that MSCs injected in the joints of mice with AIA are therapeutic, reducing inflammation, joint swelling and cartilage destruction. These cells also integrate into the synovium in AIA.
Highlights
Rheumatoid arthritis (RA) is a debilitating and painful disease leading to increased morbidity and mortality and novel therapeutic approaches are needed
Adipogenic differentiation was verified by the presence of lipid droplets stained positive with oil red O (Figure 1A), the osteogenic differentiation was detected by alkaline phosphatase (ALP) staining (Figure 1B) and chondrogenesis was confirmed by formation of dark blue/purple proteoglycan-producing pellets (Figure 1C)
In order to investigate the therapeutic effects of mesenchymal stem cells (mMSCs) we used Antigen-induced arthritis (AIA) which was induced in the right knee joints of C57Bl/6 mice (t = 0)
Summary
Rheumatoid arthritis (RA) is a debilitating and painful disease leading to increased morbidity and mortality and novel therapeutic approaches are needed. The purpose of this study was to elucidate if mesenchymal stem cells (MSCs) injected in the joints of mice with arthritis are therapeutic, reducing joint swelling and cartilage destruction. The first human trial using umbilical cord mesenchymal stem cells (UC-MSCs) was published for RA and the results confirmed the safety and efficacy of UC-MSC infusion in active RA patients [2]. MSCs have been given intravenously or intraperitonealy in animal models of RA and lead to different therapeutic effects, varying from significant improvement to no effect so overall the results remain inconclusive [5]. The reason for this may be the route of administration. Intra-articular administration of MSCs may be more beneficial than the intravenous/intraperitoneal route, applying them directly to the affected tissues
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