Mesenchymal stem cells (MSCs) are cells of a stromal origin that can self-renew and
differentiate into various lineages of mesenchymal tissues. Furthermore, MSCs exert
profound immunosuppressive effects that are superior to those of all other immunosuppressive
cell types 1]. The effects of MSCs on immune cells have mostly been studied using bone marrow-derived
MSCs (BM-MSCs). BM-MSCs have widespread effects on innate and adaptive immune cells
2]. BM-MSCs can inhibit CD4+ T-cell proliferation and B-cell differentiation and induce
the differentiation of regulatory T-cells (T-reg) 1], 3]–5]. In relation to innate immune cells, BM-MSCs suppress the generation of dendritic
cells from monocytes 6], reduce the expression of CD80 and CD86 co-stimulatory molecules on antigen-presenting
cells (APCs), and reduce the production of pro-inflammatory cytokines, such as interleukin
(IL)-2, interferon-?, and tumor necrosis factor ? (TNF?), by APCs 7].
Adipose-derived MSCs (ASCs) and BM-MSCs can both differentiate toward multiple mesodermal
tissue types, including bone, cartilage, and adipose tissue, are both immunosuppressive,
and have similar surface protein marker expression 8]–11]. However, ASCs senesce later than BM-MSCs, which may be beneficial for the treatment
of chronic or persistent conditions. ASCs have a multi-lineage differentiation capacity
and elicit immunosuppressive effects on activated immune cells 12], 13]. ASCs release growth factors that are important for wound healing, modulate the immune
system, decrease inflammation, and home to injured tissues 14]. ASCs may be of great clinical utility in regenerative therapies for Parkinson’s
disease, Alzheimer’s disease, spinal cord injury, heart diseases, and rheumatoid arthritis
(RA).
The immunosuppressive effects of ASCs are well known. In vitro, ASCs inhibit the proliferation
of activated lymphocytes via cell-cell binding and paracrine signaling 15]. Expanded ASCs have immunosuppressive properties in mice, thereby alleviating graft-versus-host-disease
and colitis 16], 17]. ASCs also have anti-inflammatory effects via inducing immune tolerance in a RA mouse
model, namely, type II collagen-induced arthritis (CIA) mice 16]. The immunosuppressive effects of ASCs in CIA were explained by Th1/Th17 suppression
and T-reg induction 16], 18].
RA involves a multicellular inflammatory process, including the infiltration of lymphocytes
and granulocytes into articular cartilage, proliferation of synovial fibroblasts and
macrophages, and neovascularization of the synovial lining of joints. Many cellular
components (macrophages, dendritic cells, neutrophils, T-cells, and B-cells), cell
surface molecules, signaling components, and humoral components interact and aid the
progression of RA 19]. CIA is the most commonly used arthritis model and is induced by type II collagen
treatment. Collagen antibody-induced arthritis (CAIA; induced by anti-type II collagen
antibodies (anti-COL II)) is another widely used mouse model 20]. The actions of anti-collagen antibodies are initiated by direct binding to their
antigens and involve immune complex formation, immune complex deposition, and activation
of complement and Fc receptors 19]. Type II collagen-specific antibodies induce arthritis in the absence of T- and B-cells
21]; therefore, CAIA is considered to be a T-cell- and B-cell-independent arthritis model,
in contrast to CIA. The suppressive effects of ASCs on arthritis are related to the
T-cell balance in CIA mice, and the effects of ASCs on other immune cells, aside from
T-cells, have not been investigated.
This study investigated the effects of human ASCs on autoimmune arthritis in CAIA
mice, which is not related to the T-cell immune response, and analyzed the influence
of ASC treatment on serum levels of adipokines in vivo.