Human Bone Marrow-Derived Mesenchymal Stromal Cells Differentially Inhibit Cytokine Production by Peripheral Blood Monocytes Subpopulations and Myeloid Dendritic Cells

Laranjeira, Pires; Gomes, Joana; Pedreiro, Susana; Pedrosa, M. Figueroa; Martinho, António; Antunes, Brígida; Ribeiro, Tania; Santos, Filipe Neves dos; Domingues, Rosário M.; Abecasis, Manuel M.; Trindade, Hélder; Paiva, Artur

doi:10.1155/2015/819084

Cited by 25 publications

(30 citation statements)

References 91 publications

(96 reference statements)

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“…ICOSL expression in MSCs has been reported by us and other groups163233. Here, we provide evidence that ICOSL expression in MSCs promotes CD4 + CD25 + FoxP3 + Treg induction.…”

Section: Discussionsupporting

confidence: 79%

ICOSL expression in human bone marrow-derived mesenchymal stem cells promotes induction of regulatory T cells

Lee

Kim

Jeon

et al. 2017

Sci Rep

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Mesenchymal stem cells (MSCs) can modulate lymphocyte proliferation and function. One of the immunomodulatory functions of MSCs involves CD4+CD25+FoxP3+ regulatory T cells (Tregs), which negatively regulate inflammatory responses. MSC-mediated Treg induction is supposed to be regulated by mechanisms requiring both soluble and cell contact-dependent factors. Although the involvement of soluble factors has been revealed, the contact-dependent mechanisms in MSC-mediated Treg induction remain unclear. We attempted to identify molecule(s) other than secreted factors that are responsible for MSC-mediated Treg induction and to uncover the underlying mechanisms. Under in vitro Treg-inducing conditions, ICOSL expression in MSCs coincided with Treg induction in co-cultures of MSCs with CD4+ T cells. When cultured in a transwell plate, MSCs failed to induce Tregs. Neutralization or knockdown of ICOSL significantly reduced Tregs and their IL-10 release. ICOSL overexpression in MSCs promoted induction of functional Tregs. ICOSL-ICOS signaling promoted Treg differentiation from CD4+ T cells through activation of the phosphoinositide 3-kinase-Akt pathway. MSCs primed with Interleukin-1β significantly induced Tregs through ICOSL upregulation. We demonstrated that the Treg-inducing activity of MSCs is proportionate to their basal ICOSL expression. This study provides evidence that ICOSL expression in human MSCs plays an important role in contact-dependent regulation of MSC-mediated Treg induction.

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“…ICOSL expression in MSCs has been reported by us and other groups163233. Here, we provide evidence that ICOSL expression in MSCs promotes CD4 + CD25 + FoxP3 + Treg induction.…”

Section: Discussionsupporting

confidence: 79%

ICOSL expression in human bone marrow-derived mesenchymal stem cells promotes induction of regulatory T cells

Lee

Kim

Jeon

et al. 2017

Sci Rep

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“…BM-MSCs exhibit significant immunomodulatory effects in vivo , modulating T-cell proliferation rates, activating a T-regulatory cell phenotype (CD8 + CD28 − Treg), and producing a general suppressive effect on CD4+ and CD8+ T cells (Castro-Manrreza and Montesinos, 2015, Liu et al, 2015). BM-MSC transplantation reduces levels of pro-inflammatory cytokines, including interleukin(IL)-1β and IL-6, upregulates the expression of anti-inflammatory cytokines, such as IL-4, IL-10, and transforming growth factor-β1, and lessens the number of activated microglia in ischemic tissue (Chen et al, 2013; McGuckin et al, 2013; Castro-Manrreza and Montesinos, 2015; Laranjeira et al, 2015). …”

Section: Identifying the Optimal Cell Type For Stem Cell Transplanmentioning

confidence: 99%

Stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms

Stonesifer

Corey

Ghanekar

et al. 2017

Progress in Neurobiology

197

207

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Ischemic stroke is a leading cause of death worldwide. A key secondary cell death mechanism mediating neurological damage following the initial episode of ischemic stroke is the upregulation of endogenous neuroinflammatory processes to levels that destroy hypoxic tissue local to the area of insult, induce apoptosis, and initiate a feedback loop of inflammatory cascades that can expand the region of damage. Stem cell therapy has emerged as an experimental treatment for stroke, and accumulating evidence supports the therapeutic efficacy of stem cells to abrogate stroke-induced inflammation. In this review, we investigate clinically relevant stem cell types, such as hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), very small embryonic-like stem cells (VSELs), neural stem cells (NSCs), extraembryonic stem cells, adipose tissue-derived stem cells, breast milk-derived stem cells, menstrual blood-derived stem cells, dental tissue-derived stem cells, induced pluripotent stem cells (iPSCs), teratocarcinoma-derived Ntera2/D1 neuron-like cells (NT2N), c-mycER(TAM) modified NSCs (CTX0E03), and notch-transfected mesenchymal stromal cells (SB623), comparing their potential efficacy to sequester stroke-induced neuroinflammation and their feasibility as translational clinical cell sources. To this end, we highlight that MSCs, with a proven track record of safety and efficacy as a transplantable cell for hematologic diseases, stand as an attractive cell type that confers superior anti-inflammatory effects in stroke both in vitro and in vivo. That stem cells can mount a robust anti-inflammatory action against stroke complements the regenerative processes of cell replacement and neurotrophic factor secretion conventionally ascribed to cell-based therapy in neurological disorders.

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“…In previous studies, we demonstrated that BM‐MSCs possess the ability to inhibit the proinflammatory response by freshly isolated myeloid dendritic cells, monocytes, and CD4 + and CD8 + T cells, regardless of the functional compartment they were included in, in healthy individuals (Laranjeira et al, ; Laranjeira et al, ). Here, we investigate whether this inhibitory effect is maintained in RA patients' immune cells.…”

Section: Introductionmentioning

confidence: 96%

Immunomodulatory effect of human bone marrow‐derived mesenchymal stromal/stem cells on peripheral blood T cells from rheumatoid arthritis patients

Pedrosa

Gomes

Laranjeira

et al. 2019

J Tissue Eng Regen Med

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Rheumatoid arthritis (RA) is a Th1/Th17‐mediated autoimmune disease whose current treatment, consisting in the blockage of inflammatory cytokines by disease‐modifying antirheumatic drugs, is not effective for all patients. The therapeutic potential of mesenchymal stromal/stem cells' (MSCs) immunomodulatory properties is being explored in RA. Here, we investigate the effect of human bone marrow (BM)‐MSCs on the expression of cytokines involved in RA physiopathology by the distinct functional compartments of CD4+ and CD8+ T cells from RA patients. Peripheral blood mononuclear cells from healthy individuals (n = 6) and RA patients (n = 12) were stimulated with phorbol myristate acetate plus ionomycin and cultured in the presence/absence of BM‐MSCs. The expression of (interleukin) IL‐2, tumor necrosis factor alpha (TNF‐α), and interferon‐gamma (IFN‐γ) was evaluated in naive, central memory, effector memory, and effector CD4+ and CD8+ T cells, whereas IL‐6, IL‐9, and IL‐17 expression was measured in total CD4+ and CD8+ T cells. mRNA expression of IL‐4, IL‐10, transforming growth factor beta (TGF‐β), cytotoxic T‐lymphocyte‐associated antigen 4, and/or forkhead box P3 was quantified in fluorescence‐activated cell sorting‐purified CD4+ T cells, CD8+ T cells, and CD4+ Treg. BM‐MSCs inhibited the production of TNF‐α, IL‐17, IL‐6, IL‐2, IFN‐γ, and IL‐9 by T cells from RA patients, mainly by reducing the percentage of cells producing cytokines. This inhibitory effect was transversal to all T cell subsets analyzed. At mRNA level, BM‐MSCs increased expression of IL‐10 and TGF‐β by CD4+ and CD8+ T cells. BM‐MSCs displayed a striking inhibitory action over T cells from RA patients, reducing the expression of cytokines involved in RA physiopathology. Remarkably, BM‐MSC‐derived immunomodulation affected either naive, effector, and memory T cells.

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Human Bone Marrow-Derived Mesenchymal Stromal Cells Differentially Inhibit Cytokine Production by Peripheral Blood Monocytes Subpopulations and Myeloid Dendritic Cells

Cited by 25 publications

References 91 publications

ICOSL expression in human bone marrow-derived mesenchymal stem cells promotes induction of regulatory T cells

ICOSL expression in human bone marrow-derived mesenchymal stem cells promotes induction of regulatory T cells

Stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms

Immunomodulatory effect of human bone marrow‐derived mesenchymal stromal/stem cells on peripheral blood T cells from rheumatoid arthritis patients

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