Local transplantation of adipose-derived stem cells has a significant therapeutic effect in a mouse model of rheumatoid arthritis

Abstract

Adipose-derived stem cells (ADSCs) have anti-inflammatory and regenerative properties. The purpose of this study was to investigate the effect of locally administered ADSCs in a rheumatoid arthritis (RA) mouse model. In an in vivo experiment, single-cell ADScs and three dimensionally-cultured ADSc spheroids were injected intra-articularly into the knees of RA model mice and histologically assessed. Marked improvement of synovial inflammation and articular cartilage regeneration was found in ADSCtreated mice. Proliferation, migration, and apoptosis assays of synovial fibroblasts incubated with single-cell and spheroid ADSCs were performed. The expression levels of total cytokine RNA in ADSC single cells, spheroids, and ADSC-treated inflammatory synovial fibroblasts were also evaluated by quantitative reverse transcription PCR. ADSCs suppressed the proliferation and migration of activated inflammatory cells and downregulated inflammatory cytokines. TSG-6 and TGFβ1 were significantly upregulated in ADScs compared to controls and TGFβ1 was significantly upregulated in ADSC spheroids compared to single cells. The apoptosis rate of ADSC spheroids was significantly lower than that of single-cell ADSCs. These results indicated that intra-articular administration of ADSC single cells and spheroids was effective in an RA mouse model, offering a novel approach for the development of effective localized treatments for patients with RA. Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and degeneration of articular cartilage and bone. In previous decades, systemic therapies, including methotrexate and biological disease-modifying antirheumatic drugs, significantly improved the treatment of synovial inflammation 1. Given that RA is a systemic disease, the focus has been to develop systemic treatments for it 2 ; however, swelling persists in some joints with such treatments and the application of systemic treatment is limited due to adverse, off-target effects. Therefore, localized treatment methods are important for treating RA. Corticosteroid injections are the most widely used localized treatment for RA. Although it reduces RA-associated synovitis, repeated intra-articular corticosteroid injections can lead to the degeneration of articular cartilage 3. Other adverse effects of corticosteroids include septic arthritis, local tissue atrophy, tendon rupture, and hyperglycaemia. Consequently, the development of safe, effective, and tissue-regenerating localized therapies must be explored. Recent studies in regenerative medicine have used mesenchymal stem cells (MSCs) derived from somatic tissues such as bone marrow, muscle, blood, and adipose tissue 4,5. MSCs exert anti-inflammatory effects, modulate the immune response, and modify the local microenvironment; furthermore, studies have reported their therapeutic effects for the treatment of inflammatory and autoimmune diseases 6,7. Considering the accessibility and ethical issues associated with the use of MSCs, adipose-derived stem cells (...

Co-Microencapsulation of Islets and MSC CellSaics, Mosaic-Like Aggregates of MSCs and Recombinant Peptide Pieces, and Therapeutic Effects of Their Subcutaneous Transplantation on Diabetes

“…It is known that MSCs secrete anti-inflammatory cytokines (IL-10, TGF-α, IDO, TSG-6, etc.) [15][16][17]31], and we have confirmed that MSC CellSaics secreted 3.1-fold more anti-inflammatory cytokine TSG-6 in response to concentration of inflammatory cytokine TNF-α than the MSC spheroids [20]. In reference [34], it is reported that transplantation of ALG-PLO microencapsulated islets trigger inflammation by increasing the TNF-α concentration at the transplantation site.…”

“…In contrast to spheroids, the spaces between the petaloid RCP pieces of the CellSaic allow for the sufficient penetration of substances into the cells, which effectively prevents cell death [13]. Mesenchymal stem cells (MSCs) are promising options as the cells comprising CellSaics for subcutaneous transplantation since they have revascularization, anti-inflammatory, and immunomodulatory abilities [14][15][16][17] and are known to enhance islet function when co-transplanted with them [18,19]. Our previous study demonstrated the continuous release of angiogenic factors and anti-inflammatory cytokines via a combination of MSCs and CellSaics (MSC CellSaics) [13,20].…”

Age affects the paracrine activity and differentiation potential of human adipose‑derived stem cells

“…However, depending on the underlying disease condition of a given patient, BMSCs may not be viable due to the risk of access or poor cell viability. Adipose tissue has been actively investigated as a promising treatment for incurable disorders (10)(11)(12)(13). ADSC therapy exhibits therapeutic effects on neurodegenerative disorders, cardiac injuries, and cutaneous damage.…”

In Vitro Cultures of Adipose-Derived Stem Cells: An Overview of Methods, Molecular Analyses, and Clinical Applications

“…Its immunosuppressive capacities are not yet fully elucidated. Nevertheless, it was noted that an ASCs' application decreased migration and proliferation of inflammatory cells, promoted the expression of anti-inflammatory cells, and downregulated the synthesis of proinflammatory cytokines, in laboratory models [70,71] The regenerative properties of ASCs have also been examined in rotator cuff repair models [72][73][74][75][76]. It has been noted that the local application of ASCs could result in less pronounced inflammation and increased bone mineral density in histologically evaluated tissues or improved their biomechanical function [72][73][74].…”