The Role of Mouse Mesenchymal Stem Cells in Differentiation of Naive T-Cells into Anti-Inflammatory Regulatory T-Cell or Proinflammatory Helper T-Cell 17 Population

Abstract

Bone marrow-derived mesenchymal stem cells (MSCs) modulate immune response and can produce significant levels of transforming growth factor-b (TGF-b) and interleukin-6 (IL-6). These 2 cytokines represent the key factors that reciprocally regulate the development and polarization of naive T-cells into regulatory T-cell (Treg) population or proinflammatory T helper 17 (Th17) cells. In the present study we demonstrate that MSCs and their products effectively regulate expression of transcription factors Foxp3 and RORgt and control the development of Tregs and Th17 cells in a population of alloantigen-activated mouse spleen cells or purified CD4 + CD25-T-cells. The immunomodulatory effects of MSCs were more pronounced when these cells were stimulated to secrete TGF-b alone or TGF-b together with IL-6. Unstimulated MSCs produce TGF-b, but not IL-6, and the production of TGF-b can be further enhanced by the anti-inflammatory cytokines IL-10 or TGF-b. In the presence of proinflammatory cytokines, MSCs secrete significant levels of IL-6, in addition to a spontaneous production of TGF-b. MSCs producing TGF-b induced preferentially expression of Foxp3 and activation of Tregs, whereas MSC supernatants containing TGF-b together with IL-6 supported RORgt expression and development of Th17 cells. The effects of MSC supernatants were blocked by the inclusion of neutralization monoclonal antibody anti-TGF-b or anti-IL-6 into the culture system. The results showed that MSCs represent important players that reciprocally regulate the development and differentiation of uncommitted naive T-cells into anti-inflammatory Foxp3 + Tregs or proinflammatory RORgt + Th17 cell population and thereby can modulate autoimmune, immunopathological, and transplantation reactions.

The Key Role of Insulin-Like Growth Factor I in Limbal Stem Cell Differentiation and the Corneal Wound-Healing Process

“…The first-strand cDNA was synthesized using random primers (Promega, Madison, WI) in a total reaction volume of 25 mL using M-MLV Reverse Transcriptase (Promega). Quantitative real-time PCR was performed in an iCycler (BioRad, Hercules, CA), as previously described [25,26]. The primers used for amplification are shown in Table 1.…”

The effect of mesenchymal stem cells on dynamic changes of T cell subsets in experimental autoimmune uveoretinitis

“…These immunosuppressive properties have been exploited extensively in a number of experimental autoimmune diseases and translated recently to the clinical setting in several diseases, such as systemic lupus erythematosus (SLE) [6], Crohn's disease [7], multiple sclerosis (MS) [8], rheumatoid arthritis [9] and Sjögren's syndrome [10]. In autoimmune diseases, MSCs can inhibit both T helper type 1 (Th1) and Th17 responses and modulate the Th17/Treg balance [11,12]. Contrary to corticosteroid and immunosuppressive agents, no tissue toxicity of MSCs has been found so far, and MSCs could even enhance the ability of the host immune cells on bacterial clearance [13].…”

Negative impact of bone-marrow-derived mesenchymal stem cells on dextran sulfate sodium-induced colitis

“…MSCs produce TGF-β in the absence of stimulatory cytokines; but synthesize high levels of IL-6 in the presence of proinflammatory cytokines such [42][43][44] . Several studies, including our previous work, confirmed that MSCs can promote the expansion of Th17 cells under appropriate conditions [25,45] . In our present work, we found that MSCs did not exert significant effects in a DSS-induced IBD model.…”