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Overexpression of TGF?1 in murine mesenchymal stem cells improves lung inflammation by impacting the Th17/Treg balance in LPS-induced ARDS mice.

ABSTRACT: BACKGROUND:T helper 17 cells (Th17)/regulatory T cells (Treg), as subtypes of CD4+ T cells, play an important role in the inflammatory response of acute respiratory distress syndrome (ARDS). However, there is still a lack of effective methods to regulate the differentiation balance of Th17/Treg. It was proven that mesenchymal stem cells (MSCs) could regulate the differentiation of CD4+ T cells, but the mechanism is still unclear. TGF?1, a paracrine cytokine of MSCs, could also regulate the differentiation of Th17/Treg but is lowly expressed in MSCs. Therefore, mouse MSCs (mMSCs) overexpressing TGF?1 were constructed by lentivirus transduction and intratracheally transplanted into LPS-induced ARDS mice in our study. The aim of this study was to evaluate the therapeutic effects of mMSCs overexpressing TGF?1 on inflammation and immunoregulation by impacting the Th17/Treg balance in LPS-induced ARDS mice. METHODS:mMSCs overexpressing TGF?1 were constructed using lentiviral vectors. Then, mouse bone-marrow-derived MSCs (mBM-MSC) and mBM-MSC-TGF?1 (mBM-MSC overexpressing TGF?1) were transplanted intratracheally into ARDS mice induced by lipopolysaccharide. At 3 and 7 days after transplantation, the mice were sacrificed, and the homing of the mMSCs was assayed by ex vivo optical imaging. The relative numbers of Th17 and Treg in the lungs and spleens of mice were detected by FCM. IL-17A and IL-10 levels in the lungs of mice were analysed by western blot. Permeability and inflammatory cytokines were evaluated by analysing the protein concentration of BALF using ELISA. Histopathology of the lungs was assessed by haematoxylin and eosin staining and lung injury scoring. Alveolar lung fibrosis was assessed by Masson's trichrome staining and Ashcroft scoring. The mortality of ARDS mice was followed until 7?days after transplantation. RESULTS:The transduction efficiencies mediated by the lentiviral vectors ranged from 82.3 to 88.6%. Overexpressing TGF?1 inhibited the proliferation of mMSCs during days 5-7 (p??0.05). Compared to that in the LPS?+?mBM-MSC-NC group mice, engraftment of mMSCs overexpressing TGF?1 led to much more differentiation of T cells into Th17 or Treg (p??0.05). CONCLUSION:MSCs overexpressing TGF?1 could regulate lung inflammation and attenuate lung injuries by modulating the imbalance of Th17/Treg in the lungs of ARDS mice.

SUBMITTER: Chen J

PROVIDER: S-EPMC7374869 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Overexpression of TGFβ1 in murine mesenchymal stem cells improves lung inflammation by impacting the Th17/Treg balance in LPS-induced ARDS mice.

Chen Jianxiao J Zhang Xiwen X Xie Jianfeng J Xue Ming M Liu Ling L Yang Yi Y Qiu Haibo H

Stem cell research & therapy 20200722 1

<h4>Background</h4>T helper 17 cells (Th17)/regulatory T cells (Treg), as subtypes of CD4<sup>+</sup> T cells, play an important role in the inflammatory response of acute respiratory distress syndrome (ARDS). However, there is still a lack of effective methods to regulate the differentiation balance of Th17/Treg. It was proven that mesenchymal stem cells (MSCs) could regulate the differentiation of CD4<sup>+</sup> T cells, but the mechanism is still unclear. TGFβ1, a paracrine cytokine of MSCs, ...[more]

PMID: 32698911

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Project description:BackgroundSjögren's syndrome (SS) is a chronic, systemic autoimmune disorder characterized by sicca syndrome and/or systemic manifestations. The disease severely affects the health and life of patients, and the treatment of SS has always been a clinical challenge and essentially palliative. Mesenchymal stem cells (MSCs) have been reported to exert immunomodulatory effects and as a potential novel therapeutic strategy for SS. Labial gland-derived MSCs (LGMSCs) are a population of resident stem cells in the labial gland, first isolated by our group. Exosomes released by MSCs contain a large variety of bioactive molecules and considered to function as an extension of MSCs.MethodsLGMSCs were isolated from patients who were needed surgery to remove the lip mucocele and LGMSCs derived exosomes (LGMSC-Exos) were isolated by ultracentrifugation. The non-obese diabetic (NOD) mice were treated with LGMSCs or LGMSC-Exos by tail vein injection. The saliva flow rate of mice was determined and salivary glands were dissected and stained with hematoxylin and eosin. In vitro, peripheral blood mononuclear cells (PBMCs) from SS patients were cocultured with LGMSCs or LGMSC-Exos. Percentage of T helper 17 (Th17) cells and regulatory T (Treg) cells were determined by flow cytometry. The serum levels of cytokines in NOD mice and in the supernatant of the co-culture system by ELISA.ResultsTreatment with LGMSCs or LGMSC-Exos reduced inflammatory infiltration in the salivary glands, and restored salivary gland secretory function in NOD mice. Importantly, LGMSCs or LGMSC-Exos were demonstrated to inhibit the differentiation of Th17 cells but promote the induction of Treg cells in NOD mice and PBMCs from SS patients in vitro, accompanied by reduced interleukin 17 (IL-17), interferon gamma, and IL-6 levels and enhanced transforming growth factor beta and IL-10 secretion by T cells.ConclusionsLGMSCs are potential candidates for MSCs-based therapy and LGMSC-Exos might be utilized for establishing a new cell-free therapy against SS.

Dataset Information

Overexpression of TGF?1 in murine mesenchymal stem cells improves lung inflammation by impacting the Th17/Treg balance in LPS-induced ARDS mice.

Publications

Overexpression of TGFβ1 in murine mesenchymal stem cells improves lung inflammation by impacting the Th17/Treg balance in LPS-induced ARDS mice.

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