Dexamethasone has variable effects on mesenchymal stromal cells
Introduction
Mesenchymal stem cells, also known asmesenchymal stromal stem cells and mesenchymal stromal cells (MSC), are a heterogeneous population of cells that proliferate in vitro as plastic-adherent cells, have fibroblast-like morphology, form colonies in vitro and can differentiate into bone, cartilage and fat cells 1., 2., 3., 4.). In addition to the bone marrow stroma, MSC have been found to exist in other tissues, such as adipose (5), umbilical cord blood (6), umbilical cord (UC) (7), amniotic membrane (8), gingiva (9), thymus (10), placenta (11), synovium (12) and fetal blood and liver (13). MSC, as a type of adult stem cells, have been seen as a promising candidate for cell therapy, because of their special tissue repair and immunosuppression abilities.
MSC have been observed to suppress directly allogeneic and mitogenic T-lymphocyte proliferation 14., 15., 16.). Numerous data have shown that the MSC suppression is mediated by the production of a variety of soluble factors, such as transforming growth factor (TGF)-β and interleukin (IL)-10 (14), indoleamine 2,3-dioxygenase (IDO) (17), soluble HLA-G5 (18), inducible nitric oxide synthase (iNOS) (19), hepatocyte growth factor (HGF) and prostaglandin E (PGE2) (20,21). Other mechanisms of T-cell activity suppression include the induction of CD25 + regulatory T cells, induction of apoptosis and cell cycle arrest 22., 23., 24.).
Dexamethasone (Dex) is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant. A decade ago, it was reported that Dex has effects on MSC gene expression (25). It is accepted widely that Dex enhances the osteogenic, chondrogenic and adipogenic differentiation potential of MSC. Dex up-regulates MSC expression of alkaline phosphatase (ALP) (26), which is an early osteogenic differentiation marker (27). However, there are data showing that the effect of Dex on MSC differentiation depends on the dosage of Dex (28). At 10−7 mol/L, Dex suppresses the osteogenic differentiation of human mesenchymal stromal cells (hMSC) and induces a shift to adipogenic differentiation (29,30). Intriguingly, low-dose Dex (10−8 mol/L) maintains the cell-surface phenotype of hMSC over multiple passages (26).
Much attention has been paid to the effect of Dex on MSC proliferation and differentiation. However, the potent immunosuppression capacity is being considered as a very important feature of MSC. We show in this study that Dex is able to impair the immunosuppressive activities of UC MSC, although low-dose Dex promotes MSC proliferation and inhibits MSC apoptosis.
Section snippets
Preparation of UC-derived MSC
UC were collected from healthy full-term pregnant donors with written consent and approval by the institutional review board of the Chinese Academy of Medical Science and Peking Union Medical College (Tianjin, China). UC MSC were isolated and expanded as described previously (31). UC MSC were cultured in complete culture medium containing Dulbecco's minimum essential medium(DMEM)/F12 (1:1) (Gibco; Grand Island, NY, USA) supplemented with 10% fetal bovine serum (FBS; HyClone, Logan, UT, USA), 100
Characterization of UC MSC
MSC derived from the human UC showed positive expression (> 95%) for CD73, CD90 and CD105, but negative (< 2%) for CD34, CD45, CD11b, CD19 and HLA-DR (Figure 1). The cells possessed multipotent differentiation potential, as they could be induced to differentiate into osteoblasts, adipocytes and chondroblasts under standard in vitro differentiating conditions, as described with previous data (32,33).
Low-dose Dex maintained the surface phenotype of MSC
After 2 weeks of treatment with Dex, the expression of most surface markers (CD11b, CD19, CD34,
Discussion
Dex is a potent synthetic member of the glucocorticoid class of steroid drugs. High dosages of Dex have been used to enhance osteogenic, chondrogenic and adipogenic differentiation of MSC. In contrast, low dosages of Dex are applied to promote MSC proliferation. Obviously, different concentrations of Dex exert diverse effects on MSC proliferation. For example, 10−6 mol/L Dex suppressed proliferation of bone marrow-derived MSC, while MSC cultured in the presence of low-dose Dex maintained a
Acknowledgments
Financial support: National Nature Science Foundation of China number 30872618.
Author disclosure statement: No competing financial interests exist.
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