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Myogenic-induced mesenchymal stem cells are capable of modulating the immune response by regulatory T cells.

ABSTRACT: Cell therapy for patients who have intractable muscle disorders may require highly regenerative cells from young, healthy allogeneic donors. Mesenchymal stem cells are currently under clinical investigation because they are known to induce muscle regeneration and believed to be immune privileged, thus making them suitable for allogeneic applications. However, it is unclear whether allogeneic and myogenic-induced mesenchymal stem cells retain their immunomodulatory characteristics. Therefore, our aim was to evaluate the effects of mesenchymal stem cell differentiation on the immune characteristics of cells in vitro. We investigated the immunologic properties of mesenchymal stem cells after myogenic induction. Mesenchymal stem cells were obtained from C57BL/6 mice and the C3H/10T1/2 murine mesenchymal stem cell line. Two different 5-aza-2'-deoxycytidine doses (0.5 and 3 µM) were evaluated for their effects on mesenchymal stem cell skeletal myogenic differentiation potential, immune antigen expression, and mixed lymphocytic reactions. Using a mixed lymphocytic reaction, we determined the optimal splenocyte proliferation inhibition dose. The induction of regulatory T cells was markedly increased by the addition of 3 µM 5-aza-2'-deoxycytidine-treated mesenchymal stem cells. Myogenic-induced mesenchymal stem cells do not elicit alloreactive lymphocyte proliferative responses and are able to modulate immune responses. These findings support the hypothesis that myogenic-induced mesenchymal stem cells may be transplantable across allogeneic barriers.

SUBMITTER: Joo S

PROVIDER: S-EPMC3927963 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RationaleT-regulatory cells (Tregs) are potent immunomodulators in allergic asthma.ObjectivesWe evaluated the functional effects of Tregs by adoptively transferring naturally occurring CD4(+)CD25(+) Tregs (NTregs) and CD4(+)CD25(-) inducible Tregs (iTregs) from lung and spleens of green fluorescent protein (GFP)-transgenic Balb/c mice into cockroach-sensitized and -challenged mice.MethodsGFP-labeled NTregs and iTregs were adoptively transferred into cockroach-sensitized and -challenged mice. Airway hyperresponsiveness (AHR) to methacholine was examined using a single-chamber, whole-body plethysmograph and invasive tracheostomy.Measurements and main resultsAdoptive transfer of either NTregs or iTregs from lung or spleen reversed airway inflammation and AHR to methacholine, and the effect lasted for at least 4 weeks. GFP-labeled iTregs up-regulated CD25 and forkhead-winged transcriptional factor box protein 3 and migrated to lymph node and lung. Lung CD4(+)CD25(+) T cells isolated from each group of recipient mice were inducible costimulatory molecule-high and programmed death (PD)-1-positive; however, higher expression of PD-1 was found in the spleen iTregs (S25(-)) and lung iTregs (L25(-)) groups. Higher levels of transforming growth factor-beta and IL-10 mRNA transcripts and bronchoalveolar lavage fluid IL-10 and INF-gamma levels were observed in lung CD4(+)CD25(+) cells from the L25(-) and S25(-) cell-recipient mice than from lung NTregs (L25(+)) and spleen NTregs (S25(+)) cell-recipient mice. Adoptive transfer of either cell type significantly reduced bronchoalveolar lavage fluid IL-4, IL-5, and IL-13 levels.ConclusionsTregs reverse AHR and airway inflammation; however iTregs that differentiated into IL-10-producing CD4(+) type 1 cells in the lung exert their suppressive activity likely by higher levels of transforming growth factor-beta, IL-10, IFN-gamma, and elevated levels of PD-1 compared with NTregs. Hence, PD-1 may be a conduit for reversing AHR by Tregs and a plausible target for treating asthma.

Project description:BackgroundEffective therapeutic strategies to address intestinal complications after radiation exposure are currently lacking. Mesenchymal stem cells (MSCs), which display the ability to repair the injured intestine, have been considered as delivery vehicles for repair genes. In this study, we evaluated the therapeutic effect of hepatocyte growth factor (HGF)-gene-modified MSCs on radiation-induced intestinal injury (RIII).MethodsFemale 6- to 8-week-old mice were radiated locally at the abdomen with a single 13-Gy dose of radiation and then treated with saline control, Ad-HGF or Ad-Null-modified MSCs therapy. The transient engraftment of human MSCs was detected via real-time PCR and immunostaining. The therapeutic effects of non- and HGF-modified MSCs were evaluated via FACS to determine the lymphocyte immunophenotypes; via ELISA to measure cytokine expression; via immunostaining to determine tight junction protein expression; via PCNA staining to examine intestinal epithelial cell proliferation; and via TUNEL staining to detect intestinal epithelial cell apoptosis.ResultsThe histopathological recovery of the radiation-injured intestine was significantly enhanced following non- or HGF-modified MSCs treatment. Importantly, the radiation-induced immunophenotypic disorders of the mesenteric lymph nodes and Peyer's patches were attenuated in both MSCs-treated groups. Treatment with HGF-modified MSCs reduced the expression and secretion of inflammatory cytokines, including tumor necrosis factor alpha (TNF-?) and interferon-gamma (IFN-?), increased the expression of the anti-inflammatory cytokine IL-10 and the tight junction protein ZO-1, and promoted the proliferation and reduced the apoptosis of intestinal epithelial cells.ConclusionsTreatment of RIII with HGF-gene-modified MSCs reduces local inflammation and promotes the recovery of small intestinal histopathology in a mouse model. These findings might provide an effective therapeutic strategy for RIII.

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Myogenic-induced mesenchymal stem cells are capable of modulating the immune response by regulatory T cells.

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