Expanded Adipose-Derived Stem Cells Suppress Mixed Lymphocyte Reaction by Secretion of Prostaglandin E2

Abstract

Multipotent mesenchymal stem cells (MSCs) in adult tissue are known to be less immunogenic and immunosuppressive. Previous study showed that primary cultures of human adipose-derived stem cells (ADSCs) shared their immunomodulatory properties with other MSCs. However, whether passaged human ADSCs can retain their immunomodulatory effect after in vitro expansion remains unknown. In addition, the mechanism of ADSC-mediated immunomodulatory effect remains to be elucidated. This study aimed to investigate these issues by using passaged human ADSCs as an in vitro study model. Flow cytometry showed that passaged ADSCs expressed human leukocyte antigen (HLA) class I but not class II molecules, which could be induced to express to a high level with interferon-gamma (IFN-gamma) treatment. The study found that passaged ADSCs could not elicit lymphocyte proliferation after co-culturing with them, even after IFN-gamma treatment. In addition, either IFN-gamma-treated or non-treated ADSCs could inhibit phytohemagglutinin (PHA)-stimulated lymphocyte proliferation. Moreover, passaged ADSCs could serve as the third-party cells to inhibited two-way mixed lymphocyte reaction (MLR). Further study using a transwell system also showed that this type of immunosuppressive effect was not cell-cell contact dependent. In defining possible soluble factors, we found that passaged ADSCs significantly increased their secretion of prostaglandin E2 (PGE2), but not transforming growth factor-beta (TGF-beta) and hepatocyte growth factor (HGF), when they were co-cultured with MLR. Furthermore, the result demonstrated that only PGE2 production inhibitor indomethacine, but not TGF-beta- and HGF-neutralizing antibodies, could significantly counteract ADSC-mediated suppression on allogeneic lymphocyte proliferation. These results indicated that in vitro expanded ADSCs retain low immunogenicity and immunosuppressive effect, and PGE2 might be the major soluble factor involved in the in vitro inhibition of allogeneic lymphocyte reaction.

Treatment of experimental arthritis by inducing immune tolerance with human adipose‐derived mesenchymal stem cells

“…Similar to BM-MSCs (23,(40)(41)(42), PGE 2 and IL-10 seem to play a critical role in the suppressive effect of human AD-MSCs. Importantly, human AD-MSCs express various Toll-like receptors and become activated in response to different inflammatory mediators and bacterial products (43).…”

“…Human MSCs obtained from subcutaneous adipose tissue (AD-MSCs) have recently emerged as an attractive alternative source of MSCs for cell therapy (7,8,10,21). Large amounts of human AD-MSCs can be easily obtained from lipoaspirates from healthy donors and rapidly expanded in vitro to generate a clinically effective dosage, and recent studies have reported that human AD-MSCs share some of the immunomodulatory properties that characterize the BM-MSCs (18,22,23). Importantly, we recently found that human AD-MSCs exert profound suppressive responses on collagen-reactive T cells from RA patients through various ways (24).…”

Allogeneic and Xenogeneic Transplantation of Adipose-Derived Stem Cells in Immunocompetent Recipients Without Immunosuppressants

“…As such, it was concluded that allogeneic transplantation of BMSC and ADSC could be employed for tissue engineering [37]. In another study the lack of MHC-II expression in ADSCs was corroborated [31].…”

“…Moreover, the immunosuppressive effect appeared to require cell-cell contact. However, in 2 separate studies the cell-cell contact requirement was corroborated [30] and disputed [31], respectively. Regardless of this disagreement, the immunosuppressive effect of ADSC has been consistently observed in all subsequent relevant studies [32][33][34][35][36].…”

The Regenerative Medicine Laboratory: Facilitating Stem Cell Therapy for Equine Disease

“…MSCs secrete soluble mediators and directly interact with T-cells to modulate their activity [29,36,37]. MSCs can induce apoptosis of activated T cells, induce cell cycle arrest, decrease T-cell proliferation [30,38] and alter T cell phenotype. MSCs target T-cell subsets (CD4+, CD8+, CD2+ and CD3+ subpopulations) equally [30].…”