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Human Liver Stem Cells Suppress T-Cell Proliferation, NK Activity, and Dendritic Cell Differentiation.

Bruno S, Grange C, Tapparo M, Pasquino C, Romagnoli R, Dametto E, Amoroso A, Tetta C, Camussi G - Stem Cells Int (2016)

Bottom Line: At variance with MSCs, HLSCs did not elicit NK degranulation.Moreover, HLSCs inhibited NK degranulation against K562, a NK-sensitive target, by a mechanism dependent on HLA-G release.This study shows that HLSCs have immunomodulatory properties similar to MSCs, but, at variance with MSCs, they do not elicit a NK response.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biotechnology and Health Science, University of Torino, 10126 Torino, Italy.

ABSTRACT
Human liver stem cells (HLSCs) are a mesenchymal stromal cell-like population resident in the adult liver. Preclinical studies indicate that HLSCs could be a good candidate for cell therapy. The aim of the present study was to evaluate the immunogenicity and the immunomodulatory properties of HLSCs on T-lymphocytes, natural killer cells (NKs), and dendritic cells (DCs) in allogeneic experimental settings. We found that HLSCs inhibited T-cell proliferation by a mechanism independent of cell contact and dependent on the release of prostaglandin E2 (PGE2) and on indoleamine 2,3-dioxygenase activity. When compared with mesenchymal stromal cells (MSCs), HLSCs were more efficient in inhibiting T-cell proliferation. At variance with MSCs, HLSCs did not elicit NK degranulation. Moreover, HLSCs inhibited NK degranulation against K562, a NK-sensitive target, by a mechanism dependent on HLA-G release. When tested on DC generation from monocytes, HLSCs were found to impair DC differentiation and DCs ability to induce T-cell proliferation through PGE2. This study shows that HLSCs have immunomodulatory properties similar to MSCs, but, at variance with MSCs, they do not elicit a NK response.

No MeSH data available.


Related in: MedlinePlus

PGE2 mediates the HLSC activity on monocyte-derived DCs. (a) Cell supernatants were harvested to detect PGE2 production by ELISA after 3 and 7 days of coculture of DCs in the presence or the absence of HLSCs. ANOVA with Dunnet's multicomparison test was performed: ∗∗p < 0.001 DC+HLSC versus HLSC. (b) mRNA expression levels of Cox-1 and Cox-2 were evaluated in HLSCs and in DCs cocultured for 7 days. Cox-1 and Cox-2 expression levels were higher in HLSCs compared with DCs. Data are expressed as relative quantification (RQ) using ΔΔCt method. Normalization was made using actin as housekeeping gene. ANOVA with Dunnet's multicomparison test was performed: ∗∗p < 0.001 HLSC versus DC. (c) Mean of percentages ± SD of CD14, CD80, CD86, CD1a, CD54, and α4 and α5 integrin of positive DCs differentiated in the presence (HLSC) or in the absence (CTRL) of HLSCs or stimulated with NS-398. Results were obtained from 4 independent experiments. ANOVA with Dunnet's multicomparison test was performed: ∗p < 0.05 HLSC versus HLSC+NS-398; ∗∗p < 0.001 HLSC versus HLSC+NS-398.
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fig6: PGE2 mediates the HLSC activity on monocyte-derived DCs. (a) Cell supernatants were harvested to detect PGE2 production by ELISA after 3 and 7 days of coculture of DCs in the presence or the absence of HLSCs. ANOVA with Dunnet's multicomparison test was performed: ∗∗p < 0.001 DC+HLSC versus HLSC. (b) mRNA expression levels of Cox-1 and Cox-2 were evaluated in HLSCs and in DCs cocultured for 7 days. Cox-1 and Cox-2 expression levels were higher in HLSCs compared with DCs. Data are expressed as relative quantification (RQ) using ΔΔCt method. Normalization was made using actin as housekeeping gene. ANOVA with Dunnet's multicomparison test was performed: ∗∗p < 0.001 HLSC versus DC. (c) Mean of percentages ± SD of CD14, CD80, CD86, CD1a, CD54, and α4 and α5 integrin of positive DCs differentiated in the presence (HLSC) or in the absence (CTRL) of HLSCs or stimulated with NS-398. Results were obtained from 4 independent experiments. ANOVA with Dunnet's multicomparison test was performed: ∗p < 0.05 HLSC versus HLSC+NS-398; ∗∗p < 0.001 HLSC versus HLSC+NS-398.

Mentions: The action of MSCs on DC differentiation has been ascribed to the production of many soluble factors, of which the most important seems to be PGE2 [14]. The presence of PGE2 was quantified by ELISA assay in supernatant of DCs differentiated in the presence or the absence of HLSCs (3 and 7 day of culture) and in HLSC supernatant (Figure 6(a)). As shown in Figure 6(a), HLSCs produced PGE2 constitutively; moreover, the amount of this mediator was significantly increased in coculture with DCs. DCs cultured alone did not produce PGE2 (Figure 6(a)). mRNA levels of Cox-1 and Cox-2 were evaluated in HLSCs and DCs when cocultured. mRNA levels of Cox-1 and Cox-2 were significantly higher in HLSCs compared with DCs, suggesting that PGE2 was mainly secreted by HLSCs (Figure 6(b)).


Human Liver Stem Cells Suppress T-Cell Proliferation, NK Activity, and Dendritic Cell Differentiation.

Bruno S, Grange C, Tapparo M, Pasquino C, Romagnoli R, Dametto E, Amoroso A, Tetta C, Camussi G - Stem Cells Int (2016)

PGE2 mediates the HLSC activity on monocyte-derived DCs. (a) Cell supernatants were harvested to detect PGE2 production by ELISA after 3 and 7 days of coculture of DCs in the presence or the absence of HLSCs. ANOVA with Dunnet's multicomparison test was performed: ∗∗p < 0.001 DC+HLSC versus HLSC. (b) mRNA expression levels of Cox-1 and Cox-2 were evaluated in HLSCs and in DCs cocultured for 7 days. Cox-1 and Cox-2 expression levels were higher in HLSCs compared with DCs. Data are expressed as relative quantification (RQ) using ΔΔCt method. Normalization was made using actin as housekeeping gene. ANOVA with Dunnet's multicomparison test was performed: ∗∗p < 0.001 HLSC versus DC. (c) Mean of percentages ± SD of CD14, CD80, CD86, CD1a, CD54, and α4 and α5 integrin of positive DCs differentiated in the presence (HLSC) or in the absence (CTRL) of HLSCs or stimulated with NS-398. Results were obtained from 4 independent experiments. ANOVA with Dunnet's multicomparison test was performed: ∗p < 0.05 HLSC versus HLSC+NS-398; ∗∗p < 0.001 HLSC versus HLSC+NS-398.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4834412&req=5

fig6: PGE2 mediates the HLSC activity on monocyte-derived DCs. (a) Cell supernatants were harvested to detect PGE2 production by ELISA after 3 and 7 days of coculture of DCs in the presence or the absence of HLSCs. ANOVA with Dunnet's multicomparison test was performed: ∗∗p < 0.001 DC+HLSC versus HLSC. (b) mRNA expression levels of Cox-1 and Cox-2 were evaluated in HLSCs and in DCs cocultured for 7 days. Cox-1 and Cox-2 expression levels were higher in HLSCs compared with DCs. Data are expressed as relative quantification (RQ) using ΔΔCt method. Normalization was made using actin as housekeeping gene. ANOVA with Dunnet's multicomparison test was performed: ∗∗p < 0.001 HLSC versus DC. (c) Mean of percentages ± SD of CD14, CD80, CD86, CD1a, CD54, and α4 and α5 integrin of positive DCs differentiated in the presence (HLSC) or in the absence (CTRL) of HLSCs or stimulated with NS-398. Results were obtained from 4 independent experiments. ANOVA with Dunnet's multicomparison test was performed: ∗p < 0.05 HLSC versus HLSC+NS-398; ∗∗p < 0.001 HLSC versus HLSC+NS-398.
Mentions: The action of MSCs on DC differentiation has been ascribed to the production of many soluble factors, of which the most important seems to be PGE2 [14]. The presence of PGE2 was quantified by ELISA assay in supernatant of DCs differentiated in the presence or the absence of HLSCs (3 and 7 day of culture) and in HLSC supernatant (Figure 6(a)). As shown in Figure 6(a), HLSCs produced PGE2 constitutively; moreover, the amount of this mediator was significantly increased in coculture with DCs. DCs cultured alone did not produce PGE2 (Figure 6(a)). mRNA levels of Cox-1 and Cox-2 were evaluated in HLSCs and DCs when cocultured. mRNA levels of Cox-1 and Cox-2 were significantly higher in HLSCs compared with DCs, suggesting that PGE2 was mainly secreted by HLSCs (Figure 6(b)).

Bottom Line: At variance with MSCs, HLSCs did not elicit NK degranulation.Moreover, HLSCs inhibited NK degranulation against K562, a NK-sensitive target, by a mechanism dependent on HLA-G release.This study shows that HLSCs have immunomodulatory properties similar to MSCs, but, at variance with MSCs, they do not elicit a NK response.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biotechnology and Health Science, University of Torino, 10126 Torino, Italy.

ABSTRACT
Human liver stem cells (HLSCs) are a mesenchymal stromal cell-like population resident in the adult liver. Preclinical studies indicate that HLSCs could be a good candidate for cell therapy. The aim of the present study was to evaluate the immunogenicity and the immunomodulatory properties of HLSCs on T-lymphocytes, natural killer cells (NKs), and dendritic cells (DCs) in allogeneic experimental settings. We found that HLSCs inhibited T-cell proliferation by a mechanism independent of cell contact and dependent on the release of prostaglandin E2 (PGE2) and on indoleamine 2,3-dioxygenase activity. When compared with mesenchymal stromal cells (MSCs), HLSCs were more efficient in inhibiting T-cell proliferation. At variance with MSCs, HLSCs did not elicit NK degranulation. Moreover, HLSCs inhibited NK degranulation against K562, a NK-sensitive target, by a mechanism dependent on HLA-G release. When tested on DC generation from monocytes, HLSCs were found to impair DC differentiation and DCs ability to induce T-cell proliferation through PGE2. This study shows that HLSCs have immunomodulatory properties similar to MSCs, but, at variance with MSCs, they do not elicit a NK response.

No MeSH data available.


Related in: MedlinePlus