Role for Interferon-γ in the Immunomodulatory Activity of Human Bone Marrow Mesenchymal Stem Cells

Krampera, Mauro; Cosmi, Lorenzo; Angeli, Roberta; Pasini, Anna Fratta; Liotta, Francesco; Andreini, Angelo; Santarlasci, Veronica; Mazzinghi, Benedetta; Pizzolo, Giovanni; Vinante, Fabrizio; Romagnani, Paola; Maggi, Enrico; Romagnani, Sergio; Annunziato, Francesco

doi:10.1634/stemcells.2005-0008

Cited by 1,195 publications

(1,149 citation statements)

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“…Despite the general consensus concerning the capacity of MSC to inhibit proliferation of T lymphocytes, little is known on the molecular mechanism(s) responsible for this effect. Thus, it did not appear to be dependent on the induction of apoptosis of proliferating cells [13,16,39]. Inhibition of cell division could be a possible explanation since accumulation of cells in the G 0 phase of the cell cycle has been detected [45].…”

Section: Msc and T Lymphocytesmentioning

confidence: 97%

“…Despite the current lack of information on Toll-like receptor (TLR) expression, MSC are profoundly influenced by microenvironmental factors and can respond to some inflammatory cytokines such as IL-1b [37], IL-17 [38] and (more importantly) IFN-c, all capable of significantly affecting their function. In this context, it is worth stressing that while under some circumstances IFN-c appears to enhance the immunosuppressive activity of human MSC [39], in other cases it can induce MSC to act even as non-conventional antigen-presenting cells (APC) [17,40]. These data are of great importance in view of the potential utilization of MSC for therapeutic purposes.…”

Section: Immunological Phenotype and Functions Of Mscmentioning

confidence: 99%

“…Inhibition of cell division could be a possible explanation since accumulation of cells in the G 0 phase of the cell cycle has been detected [45]. In addition, suppression of T cell proliferation induced by human MSC appears to depend, at least in part, on the cross-talk between the two cell populations, leading to the production of inflammatory cytokines such as IFN-c [39] and IL-1b [37] by activated immune cells. Inhibition of T cell proliferation resulted in the decreased production of effector Th1 cytokines [16,42,46]; however, the expression of activation markers in T cells that have been cultured with MSC remains a controversial issue [39,43,45,47].…”

Section: Msc and T Lymphocytesmentioning

confidence: 99%

“…In addition, suppression of T cell proliferation induced by human MSC appears to depend, at least in part, on the cross-talk between the two cell populations, leading to the production of inflammatory cytokines such as IFN-c [39] and IL-1b [37] by activated immune cells. Inhibition of T cell proliferation resulted in the decreased production of effector Th1 cytokines [16,42,46]; however, the expression of activation markers in T cells that have been cultured with MSC remains a controversial issue [39,43,45,47]. Inhibition of T cell proliferation by MSC appears to be subsequent both to cell-to-cell interaction and to the release of soluble factors, and it is conceivable that discrepant findings reported in the literature reflect differences in the experimental conditions used [13,14,16,48,49].…”

Section: Msc and T Lymphocytesmentioning

confidence: 99%

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Immunoregulatory function of mesenchymal stem cells

2006

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Mesenchymal stem cells (MSC) are a rare subset of stem cells residing in the bone marrow where they closely interact with hematopoietic stem cells and support their growth and differentiation. MSC can differentiate into multiple mesenchymal and non‐mesenchymal lineages, providing a promising tool for tissue repair. In addition, MSC suppress many T cell, B cell and NK cell functions and may affect also dendritic cell activities. Due to their limited immunogenicity, MSC are poorly recognized by HLA‐incompatible hosts. Based on these unique properties, MSC are currently under investigation for their possible use to treat immuno‐mediated diseases. However, both their condition of immunoprivilege and their immunosuppressive function have recently been challenged when analyzed under particular experimental conditions. Thus, it is likely that MSC effects on the immune system may be deeply influenced not only by cell‐to‐cell interactions, but also by environmental factors shaping their phenotype and functions.

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Section: Msc and T Lymphocytesmentioning

confidence: 97%

Section: Immunological Phenotype and Functions Of Mscmentioning

confidence: 99%

Section: Msc and T Lymphocytesmentioning

confidence: 99%

Section: Msc and T Lymphocytesmentioning

confidence: 99%

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Immunoregulatory function of mesenchymal stem cells

2006

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“…Systemically transferred MSCs, for example, can also migrate into tumor tissue such as colon carcinomas or glioblastoma 13, 14. MSCs can act as immunoregulatory cells, releasing IL‐10 and prostaglandin E2, or by expressing the enzyme indoleamine 2,3‐dioxygenase (IDO) 15, 16, 17…”

Section: Introductionmentioning

confidence: 99%

ATP promotes immunosuppressive capacities of mesenchymal stromal cells by enhancing the expression of indoleamine dioxygenase

Lotfi

Steppe

Hang

et al. 2018

Immunity Inflam & Disease

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IntroductionMSCs are often found within tumors, promote cancer progression and enhance metastasis. MSCs can act as immuosuppressive cells, partially due to the expression of the enzyme indoleamine dioxygenase (IDO) which converts tryptophan to kynurenine. Decreased concentration of tryptophan and increased kynurenine, both interfere with effective immune response. Damage associated molecular patterns (DAMPs) including ATP are found within the tumor microenvironment, attract MSCs, and influence their biology.MethodsBone marrow derived MSCs were exposed to ATP for 4 days, in the presence of 100 ng IFNγ/mL. Intracellular expression of IDO in MSCs was assessed by FACS. Conditioned media from thus stimulated MSCs was analyzed for kynurenine content and its suppressive effect on lymphocyte proliferation. Apyrase or P2 × 7‐receptor antagonist (AZ 11645373) were applied in order to inhibit ATP induced effect on MSCs.ResultsWe demonstrate, that ATP at concentrations between 0.062 and 0.5 mM increases dose dependently the expression of IDO in MSCs with subsequent increased kynurenine concentrations within the supernatant at about 60%. This effect could be abolished completely in the presence of ATP degrading enzyme (apyrase) or when MSCs were pretreated with a P2 × 7‐receptor antagonist (AZ 11645373). Consistently, supernatants from MSCs stimulated with ATP, inhibited lymphocyte proliferation from 65% to 16%.ConclusionsWe characterized ATP as a DAMP family member responsible for necrosis‐induced immunomodulation. Given the increased concentration of DAMPs within tumor tissue and the fact that DAMPs can act as chemotattractants to MSCs, our results have implications for therapeutic strategies targeting the tumor microenvironment.

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Mesenchymal stromal cells derived from whole human umbilical cord exhibit similar properties to those derived from Wharton's jelly and bone marrow

et al. 2016

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Mesenchymal stromal cells (MSC) can be isolated from several regions of human umbilical cords, including Wharton's jelly (WJ), artery, vein or cord lining. These MSC appear to be immune privileged and are promising candidates for cell therapy. However, isolating MSC from WJ, artery, vein or cord lining requires time‐consuming tissue dissection. MSC can be obtained easily via briefly digesting complete segments of the umbilical cord, likely containing heterogenous or mixed populations of MSC (MC‐MSC). MC‐MSC are generally less well characterized than WJ‐MSC, but nevertheless represent a potentially valuable population of MSC. This study aimed to further characterize MC‐MSC in comparison to WJ‐MSC and also the better‐characterized bone marrow‐derived MSC (BM‐MSC). MC‐MSC proliferated faster, with significantly faster doubling times reaching passage one 8.8 days sooner and surviving longer in culture than WJ‐MSC. All MSC retained the safety aspect of reducing telomere length with increasing passage number. MSC were also assessed for their ability to suppress T‐cell proliferation and for the production of key markers of pluripotency, embryonic stem cells, tolerogenicity (CD40, CD80, CD86 and HLA‐DR) and immunomodulation (indoleamine 2,3‐dioxygenase [IDO] and HLA‐G). The MC‐MSC population displayed all of the positive attributes of WJ‐MSC and BM‐MSC, but they were more efficient to obtain and underwent more population doublings than from WJ, suggesting that MC‐MSC are promising candidates for allogeneic cell therapy in regenerative medicine.

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Role for Interferon-γ in the Immunomodulatory Activity of Human Bone Marrow Mesenchymal Stem Cells

Abstract: STEM CELLS 2006;24: 386 -398

Cited by 1,195 publications

References 52 publications

Immunoregulatory function of mesenchymal stem cells

Immunoregulatory function of mesenchymal stem cells

ATP promotes immunosuppressive capacities of mesenchymal stromal cells by enhancing the expression of indoleamine dioxygenase

Mesenchymal stromal cells derived from whole human umbilical cord exhibit similar properties to those derived from Wharton's jelly and bone marrow

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