Dataset Information

Wip1 regulates the immunomodulatory effects of murine mesenchymal stem cells in type 1 diabetes mellitus via targeting IFN-α/BST2

ABSTRACT: Mesenchymal stem cells (MSCs) show significant therapeutic effects in type 1 diabetes mellitus (T1DM) as regulating the inflammatory processes. However, little is known about the detailed process of MSCs immunosuppression in T1DM. In this study, we investigated the effects of wild-type p53-induce phosphatase 1 (Wip1) on regulating MSCs immunosuppressive capacities in T1DM mice. We found that Wip1 knockout (Wip1−/−) MSCs had lower therapeutic effects in T1DM mice, and displayed weaker immunosuppressive capability. In vivo distribution analysis results indicated that Wip1−/−MSCs could home to the damaged pancreas and increase the expression of tumor necrosis factor-α (TNF-α), interleukin-17a (IL-17a), interferon-α(IFN-α), IFN-β, and IFN-γ, while decrease the expression of IL-4 and IL-10. Moreover, we confirmed Wip1−/−MSCs exhibited weaker immunosuppressive capacity, as evidenced by enhanced expression of bone marrow stromal cell antigen 2(BST2) and IFN-α. In conclusion, these results revealed Wip1 affects MSCs immunomodulation by regulating the expression of IFN-α/BST2. Our study uncovered that Wip1 is required to regulate the therapeutic effects of MSCs on T1DM treatment, indicating a novel role of Wip1 in MSCs immunoregulation properties.

SUBMITTER: Zhou N

PROVIDER: S-EPMC8556269 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Many long non-coding RNAs (lncRNAs) are expressed in cells but only a few have been well characterized. In these cases, lncRNAs have been shown to be key regulators of several cellular processes. Therefore, there is a great need to understand the function of more lncRNAs and their regulation in response to stimuli. Interferon (IFN) is a key molecule in the cellular antiviral response. IFN binding to its receptor activates transcription of several IFN-stimulated genes (ISGs) that function as potent antivirals. In addition, several ISGs are positive or negative regulators of the IFN pathway. This is essential to ensure a strong antiviral response and a later return of the cell to homeostasis. As the ISGs described to date are coding genes, we sought to determine whether IFN also regulates the expression of long non-coding ISGs. To this aim, we used RNA sequencing to analyze the transcriptome of control and HuH7 cells treated with IFN?2. The results show that IFN-treatment regulates the expression of several unknown non-coding transcripts. We have validated two lncRNAs upregulated after treatment with different doses of type I IFN?2 in different cells or with type III IFN?. These lncRNAs were also induced by influenza and vesicular stomatitis virus mutants unable to block the IFN response, but not by several wild-type lytic viruses tested. These lncRNA genes were named lncISG15 and lncBST2 as they are located close to ISGs ISG15 and BST2, respectively. Interestingly, inhibition experiments showed that lncBST2 is a positive regulator of BST2. Therefore lncBST2 has been renamed BISPR, from BST2 IFN-stimulated positive regulator. Our results may have therapeutic implications as lncBST2/BISPR, but also lncISG15 and their coding neighbors, are increased in cells infected with hepatitis C virus and in the liver of infected patients. These results allow us to hypothesize that several lncRNAs could be activated by IFN to control the potency of the antiviral IFN response.

Project description:Recently, it has been observed that mesenchymal stem cells (MSCs) can modulate their immunoregulatory properties depending on the specific in-vitro activation of different Toll-like receptors (TLR), such as TLR3 and TLR4. In the present study, we evaluated the effect of polyinosinic:polycytidylic acid (poly(I:C)) and lipopolysaccharide (LPS) pretreatment on the immunological capacity of MSCs in vitro and in vivo.C57BL/6 bone marrow-derived MSCs were pretreated with poly(I:C) and LPS for 1 hour and their immunomodulatory capacity was evaluated. T-cell proliferation and their effect on Th1, Th17, and Treg differentiation/activation were measured. Next, we evaluated the therapeutic effect of MSCs in an experimental autoimmune encephalomyelitis (EAE) model, which was induced for 27 days with MOG35-55 peptide following the standard protocol. Mice were subjected to a single intraperitoneal injection (2?×?106 MSCs/100 ?l) on day 4. Clinical score and body weight were monitored daily by blinded analysis. At day 27, mice were euthanized and draining lymph nodes were extracted for Th1, Th17, and Treg detection by flow cytometry.Pretreatment of MSCs with poly(I:C) significantly reduced the proliferation of CD3+ T cells as well as nitric oxide secretion, an important immunosuppressive factor. Furthermore, MSCs treated with poly(I:C) reduced the differentiation/activation of proinflammatory lymphocytes, Th1 and Th17. In contrast, MSCs pretreated with LPS increased CD3+ T-cell proliferation, and induced Th1 and Th17 cells, as well as the levels of proinflammatory cytokine IL-6. Finally, we observed that intraperitoneal administration of MSCs pretreated with poly(I:C) significantly reduced the severity of EAE as well as the percentages of Th1 and Th17 proinflammatory subsets, while the pretreatment of MSCs with LPS completely reversed the therapeutic immunosuppressive effect of MSCs.Taken together, these data show that pretreatment of MSCs with poly(I:C) improved their immunosuppressive abilities. This may provide an opportunity to better define strategies for cell-based therapies to autoimmune diseases.

Dataset Information

Wip1 regulates the immunomodulatory effects of murine mesenchymal stem cells in type 1 diabetes mellitus via targeting IFN-α/BST2

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets