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Treg regulation of the epithelial stem cell lineage.

ABSTRACT: Tissue repair and maintenance in adult organisms is dependent on the interactions between stem cells (SCs) and constituent cells of their microenvironment, or niche. Accumulating evidence suggests that immune cells, specifically Foxp3+ CD4+ Regulatory T cells (Tregs), play an important role as a regulator of the SC niche. Undisputedly, Tregs are the major immunosuppressive lineage of the CD4+ T cell compartment, and reside within numerous secondary lymphoid organs, where they exert their functions. These cells are also specialised in facilitating protective functions specific to their tissue of residence. In this review, we discuss the emerging concepts supporting the SC-regulatory functions of tissue-resident Tregs, during both the steady-state and SC-mediated regeneration. We highlight the skin, intestines, and lung as model organs which are subject to recurrent microinjury,exposure to microbiota, and constantly replenished by resident stem cell populations. An in-depth understanding of the biology of the Treg-SC axis will inform ongoing immunotherapeutic endeavours to target specific subpopulations of tissue-resident Tregs.

SUBMITTER: Cho I

PROVIDER: S-EPMC7226844 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Treg regulation of the epithelial stem cell lineage.

Cho Inchul I Lui Prudence Pokwai PP Ali Niwa N

Journal of immunology and regenerative medicine 20200601

Tissue repair and maintenance in adult organisms is dependent on the interactions between stem cells (SCs) and constituent cells of their microenvironment, or niche. Accumulating evidence suggests that immune cells, specifically Foxp3+ CD4+ Regulatory T cells (Tregs), play an important role as a regulator of the SC niche. Undisputedly, Tregs are the major immunosuppressive lineage of the CD4+ T cell compartment, and reside within numerous secondary lymphoid organ ...[more]

PMID: 32494759

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Project description:Background & objectivesMesencymal stem cells (MSCs) derived from foetal tissues present a multipotent progenitor cell source for application in tissue engineering and regenerative medicine. The present study was carried out to derive foetal mesenchymal stem cells from ovine source and analyze their differentiation to osteogenic linage to serve as an animal model to predict human applications.MethodsIsolation and culture of sheep foetal bone marrow cells were done and uniform clonally derived MSC population was collected. The cells were characterized using cytochemical, immunophenotyping, biochemical and molecular analyses. The cells with defined characteristics were differentiated into osteogenic lineages and analysis for differentiated cell types was done. The cells were analyzed for cell surface marker expression and the gene expression in undifferentiated and differentiated osteoblast was checked by reverse transcriptase PCR (RT PCR) analysis and confirmed by sequencing using genetic analyzer.ResultsOvine foetal samples were processed to obtain mononuclear (MNC) cells which on culture showed spindle morphology, a characteristic oval body with the flattened ends. MSC population CD45⁻/CD14⁻ was cultured by limiting dilution to arrive at uniform spindle morphology cells and colony forming units. The cells were shown to be positive for surface markers such as CD44, CD54, integrinβ1, and intracellular collagen type I/III and fibronectin. The osteogenically induced MSCs were analyzed for alkaline phosphatase (ALP) activity and mineral deposition. The undifferentiated MSCs expressed RAB3B, candidate marker for stemness in MSCs. The osteogenically induced and uninduced MSCs expressed collagen type I and MMP13 gene in osteogenic induced cells.Interpretation & conclusionsThe protocol for isolation of ovine foetal bone marrow derived MSCs was simple to perform, and the cultural method of obtaining pure spindle morphology cells was established. Criteria proposed for defining MSCs by this study includes the cell adherence to culture plates, specific surface protein profiles and differentiation to osteogenic lineage. The MSCs and osteogenic differentiated cells in this ovine animal model may serve as a large source for stem cell applications in regenerative medical therapies.

Project description:Background and objectiveUmbilical cord (UC)-derived mesenchymal stem cells (MSCs) have shown immunoregulation of various immune cells. The aim of this study was to investigate the mechanism of UC MSCs in the regulation of peripheral regulatory T cells (Treg) and T helper 17 (Th17) cells in patients with systemic lupus erythematosus (SLE).MethodsThirty patients with active SLE, refractory to conventional therapies, were given UC MSCs infusions. The percentages of peripheral blood CD4+CD25+Foxp3+ regulatory T cells (Treg) and CD3+CD8-IL17A+ Th17 cells and the mean fluorescence intensities (MFI) of Foxp3 and IL-17 were measured at 1 week, 1 month, 3 months, 6 months, and 12 months after MSCs transplantation (MSCT). Serum cytokines, including transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and IL-17A were detected using ELISA. Peripheral blood mononuclear cells from patients were collected and co-cultured with UC MSCs at ratios of 1:1, 10:1, and 50:1, respectively, for 72 h to detect the proportions of Treg and Th17 cells and the MFIs of Foxp3 and IL-17 were determined by flow cytometry. The cytokines in the supernatant solution were detected using ELISA. Inhibitors targeting TGF-β, IL-6, indoleamine 2,3-dioxygenase (IDO), and prostaglandin E2 were added to the co-culture system, and the percentages of Treg and Th17 cells were observed.ResultsThe percentage of peripheral Treg and Foxp3 MFI increased 1 week, 1 month, and 3 months after UC MSCs transplantation, while the Th17 proportion and MFI of IL-17 decreased 3 months, 6 months, and 12 months after the treatment, along with an increase in serum TGF-β at 1 week, 3 months, and 12 months and a decrease in serum TNF-α beginning at 1 week. There were no alterations in serums IL-6 and IL-17A before or after MSCT. In vitro studies showed that the UC MSCs dose-dependently up-regulated peripheral Treg proportion in SLE patients, which was not depended on cell-cell contact. However, the down-regulation of Th17 cells was not dose-dependently and also not depended on cell-cell contact. Supernatant TGF-β and IL-6 levels significantly increased, TNF-α significantly decreased, but IL-17A had no change after the co-culture. The addition of anti-TGF-β antibody significantly abrogated the up-regulation of Treg, and the addition of PGE2 inhibitor significantly abrogated the down-regulation of Th17 cells. Both anti-IL-6 antibody and IDO inhibitor had no effects on Treg and Th17 cells.ConclusionsUC MSCs up-regulate Treg and down-regulate Th17 cells through the regulation of TGF-β and PGE2 in lupus patients.

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Treg regulation of the epithelial stem cell lineage.

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Treg regulation of the epithelial stem cell lineage.

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