The interaction between mesenchymal stem cells and steroids during inflammation

Abstract

Mesenchymal stem cells (MSCs) are believed to exert their regenerative effects through differentiation and modulation of inflammatory responses. However, the relationship between the severity of inflammation and stem cell-mediated tissue repair has not been formally investigated. In this study, we applied different concentrations of dexamethasone (Dex) to anti-CD3-activated splenocyte cultured with or without MSCs. As expected, Dex exhibited a classical dose-dependent inhibition of T-cell proliferation. Surprisingly, although MSCs also blocked T-cell proliferation, the presence of Dex unexpectedly showed a dose-dependent reversion of T-cell proliferation. This effect of Dex was found to be exerted through interfering STAT1 phosphorylation-prompted expression of inducible nitric oxide synthase (iNOS). Interestingly, inflammation-induced chemokines in MSCs was unaffected. To test the role of inflammation severity in stem cell-mediated tissue repair, we employed mice with carbon tetrachloride-induced advanced liver fibrosis and found that although MSCs alone were effective, concurrent administration of Dex abrogated the therapeutic effects of MSCs on fibrin deposition, serum levels of bilirubin, albumin, and aminotransferases, as well as T-lymphocyte infiltration, especially IFN-γ+CD4+ and IL-17A+CD4+T cells. Likewise, iNOS−/− MSCs, which produce chemokines but not nitric oxide under inflammatory conditions, are ineffective in treating advanced liver fibrosis. Therefore, inflammation has a critical role in MSC-mediated tissue repair. In addition, concomitant application of MSCs with steroids should be avoided.

Mesenchymal stem cells and adaptive immune responses

“…Similar inhibition of T cell activity was also observed in murine MSCs [23]. In fact, MSCs can induce anergy in T cells by profoundly inhibiting cyclin D2 expression and inhibit the proliferation in both CD4 + and CD8 + T cells through releasing nitric oxide [24,25] Furthermore, MSCs also exerted beneficial effect on patients suffering from autoimmune and inflammatory diseases through suppressing immune responses, including experimental autoimmune encephalomyelitis (EAE) [36], collagen induced arthritis (CIA) [37], diabetes [38], lupus [39], liver fibrosis [40], delayed type hypersensitivity (DTH) [41], acute pancreatitis [42], and renal failure [43], etc. More importantly, MSCs showed promising effect on treating graft versus host diseases [24].…”

“…The MSC-mediated suppression on T cells in in vitro culture system [40]. The presence of dexamethasone abolished the therapeutic effect of MSCs on liver fibrosis, embodying as sustained aberrant T cell responses [40].…”

“…The MSC-mediated suppression on T cells in in vitro culture system [40]. The presence of dexamethasone abolished the therapeutic effect of MSCs on liver fibrosis, embodying as sustained aberrant T cell responses [40]. Therefore, the amounts and kinds of cytokines, as well as immunosuppressants in the inflammatory environment dictate MSCs' ability to inhibit or promote immune responses (Fig.2).…”

Mesenchymal stromal cells and liver fibrosis: a complicated relationship

“…Chen et al . (86) injected 0.5 × 10 6 syngeneic BM‐MSCs on the last 2 d of a 61‐d hepatic injury (twice per week CCl 4 by oral gavage), then analyzed the effects 3 and 6 d later. Morphometric analysis of CPA showed that the MSC‐treated group had a significant reduction in fibrosis compared with the untreated group (4 vs. 7%; P < 0.001), with a significant reduction in α‐SMA–postive cell staining by IHC (4 vs .…”

Mesenchymal stromal cells and chronic inflammatory bowel disease

“…By contrast, it has been recently described the case of a patient suffering from childhood-onset, multidrug-resistant form of CD, in which IFN-γ pre-treatment of MSCs before infusion has not determined clinical benefit [110]. MSCs should be avoided [112]. Further investigation into the underlying molecular mechanisms is warranted to allow more effective manipulation of MSC function for clinical applications.…”