Enhancement of the immunoregulatory potency of mesenchymal stromal cells by treatment with immunosuppressive drugs

Girdlestone, John; Pido-Lopez, Jeffrey; Srivastava, Saket; Chai, Jian-Guo; Leaver, Neil; Galleu, Antonio; Lombardi, Giovanna; Navarrete, Cristina

doi:10.1016/j.jcyt.2015.05.009

Cited by 29 publications

(37 citation statements)

References 43 publications

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“…Some studies have indicated that rapamycin, an immunosuppressive drug, could enhance the immunoregulatory potency of pretreated MSCs through subsequent diffusion into cocultures [38]. We showed a similar result in the rapamycin group; however, this result may have been caused by the elevated autophagy level of MSCs.…”

Section: Discussionsupporting

confidence: 70%

Autophagy Improves the Immunosuppression of CD4+ T Cells by Mesenchymal Stem Cells Through Transforming Growth Factor-β1

Gao

Cen

Wang

et al. 2016

Stem Cells Translational Medicine

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Mesenchymal stem cells (MSCs) have been extensively investigated as a promising approach to treat many autoimmune and inflammatory diseases. The stress condition would affect the therapeutic efficacy and induce autophagy of MSCs. However, whether autophagy would affect the immunosuppressive capacity of MSCs is largely unknown. The present study aimed to assess whether autophagy plays an important role in regulating the immunomodulation of MSCs and the undermechanisms. We successfully inhibited and induced autophagy of MSCs using 3-methyladenine (3-MA) and rapamycin, respectively. Our results demonstrated that rapamycin strengthened the capacity of MSCs to inhibit CD4 + T-cell proliferation, whereas 3-MA weakened the inhibitory ability of MSCs. Mechanistically, 3-MA-pretreated MSCs secreted less, whereas rapamycin-pretreated MSCs secreted more transforming growth factor-b1 (TGF-b1) compared with the control cells. Furthermore, exogenous TGF-b1 addition recovered the immunosuppressive capacity of 3-MA-pretreated MSCs, whereas exogenous anti-TGF-b1 antibody addition reduced the immunosuppressive capacity of rapamycin-pretreated MSCs. These results indicated that the autophagy level regulates the immunosuppression of CD4 + T cells by MSCs through affecting TGF-b1 secretion and provides a novel method for improving the therapeutic efficacy of MSCs by activating autophagy. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1496-1505 SIGNIFICANCEMesenchymal stem cell (MSC)-based therapy is a promising tool to treat many diseases. Autophagy occurred in MSCs during their application, especially in those exposed to stress conditions. However, whether autophagy will affect the therapeutic efficacy of MSCs is largely unknown. This study makes a significant contribution to demonstrate that autophagy could improve the immunosuppression of CD4 + T cells by mesenchymal stem cells through transforming growth factor-b1. Therefore, regulation of autophagy in MSCs would provide a promising strategy to improve the therapeutic efficacy of these cells.

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Section: Discussionsupporting

confidence: 70%

Autophagy Improves the Immunosuppression of CD4+ T Cells by Mesenchymal Stem Cells Through Transforming Growth Factor-β1

Gao

Cen

Wang

et al. 2016

Stem Cells Translational Medicine

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“…A high dose of CyA can then be used to overcome this. In contrast, several studies have reported various synergistic tolerogenic effects of MSCs and immunosuppressive drugs [404][405][406][407] . We therefore combined DSCs and CyA or SRL in MLRs, and measured proliferation between days 5 and 6 of incubation.…”

Section: 360mentioning

confidence: 99%

Decidual Stromal Cells Promote Regulatory T Cells and Suppress Alloreactivity in a Cell Contact-Dependent Manner

Erkers

Nava

Yosef

et al. 2013

Stem Cells and Development

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Acute graft-versus-host disease (GvHD) is a severe adverse event after stem cell transplantation. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) have been used to treat GvHD, but decidual stromal cells (DSCs) isolated from term fetal membrane have advantages compared with BM-MSCs, including increased allosuppression, unlimited supply, and high expression of integrins. We introduced the use of DSCs in patients with steroid refractory aGvHD. In this study, we investigated factors of importance in the reduction of alloreactivity by DSCs. We found that DSCs need to have cell-cell contact in order to mediate suppression in mixed lymphocyte reactions (MLRs). This contact dependency is consistent with an increased frequency of CD4(+)CD25(high)FOXP3(+) regulatory T cells (Tregs) and an augmented intensity of CD25 expression in CD4(+) T cells. Blocking of the activity of indoleamine-2,3-dioxygenase (IDO), prostaglandin E2, PD-L1, and IFN-γ impaired the antiproliferative ability of the DSCs in MLRs. Neutralization of IDO also reduced the frequency of Tregs. In contrast to BM-MSCs, pretreatment of DSCs with high concentrations of IFN-γ (100 U/mL) reduced their ability to suppress alloreactivity, but stimulation of DSCs with MLR supernatants containing low levels of IFN-γ had no effect on the suppressive capacity in MLR. To conclude, DSCs differ in several aspects from MSCs and need to be close to alloreactive lymphocytes to mediate a suppressive effect and increase the frequency of Tregs. Thus, DSCs may not only use paracrine factors for systemic immunosuppression, but also more specifically target T cells locally in affected tissues.

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“…Some studies suggested that MSC can act as drug delivery system. In a recent report it has been shown the capacity of a brief exposure to immunosuppressive drugs to improve the immunoregulatory potency of MSC [27]. In our model, the results suggest that BM-MSC from MPN patients with JAK2V617F mutation does not act as a carrier of the inhibitor but as a specific target for PCI34051.…”

Section: Discussionmentioning

confidence: 64%

HDAC8 overexpression in mesenchymal stromal cells from JAK2+ myeloproliferative neoplasms: a new therapeutic target?

et al. 2017

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Histone deacetylases (HDACs) are involved in epigenetic modulation and their aberrant expression has been demonstrated in myeloproliferative neoplasms (MPN). HDAC8 inhibition has been shown to inhibit JAK2/STAT5 signaling in hematopoietic cells from MPN. Nevertheless, the role of HDAC8 expression in bone marrow-mesenchymal stromal cells (BM-MSC) has not been assessed. In the current work we describe that HDAC8 is significantly over-expressed in MSC from in JAK-2 positive MPN compared to those from healthy-donors (HD-MSC). Using a selective HDAC8 inhibitor (PCI34051), we verified that the subsequent decrease in the protein and mRNA expression of HDAC8 is linked with an increased apoptosis of malignant MSC whereas it has no effects on normal MSC. In addition, HDAC8 inhibition in MPN-MSC also decreased their capacity to maintain neoplastic hematopoiesis, by increasing the apoptosis, cell-cycle arrest and colony formation of JAK2+-hematopoietic cells. Mechanistic studies using different MPN cell lines revealed that PCI34051 induced their apoptosis, which is enhanced when were co-cultured with JAK2V617F-MSC, decreased their colony formation and the phosphorylation of STAT3 and STAT5. In summary, we show for the first time that the inhibition of HDAC8 in MSC from JAK2+ MPN patients selectively decreases their hematopoietic-supporting ability, suggesting that HDAC8 may be a potential therapeutic target in this setting by acting not only on hematopoietic cells but also on the malignant microenvironment.

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Enhancement of the immunoregulatory potency of mesenchymal stromal cells by treatment with immunosuppressive drugs

Abstract: The use of treated MSCs may achieve clinical end points not reached with untreated MSCs and allow for infusion of fewer cells to reduce costs and minimize potential side effects.

Cited by 29 publications

References 43 publications

Autophagy Improves the Immunosuppression of CD4+ T Cells by Mesenchymal Stem Cells Through Transforming Growth Factor-β1

Autophagy Improves the Immunosuppression of CD4+ T Cells by Mesenchymal Stem Cells Through Transforming Growth Factor-β1

Decidual Stromal Cells Promote Regulatory T Cells and Suppress Alloreactivity in a Cell Contact-Dependent Manner

HDAC8 overexpression in mesenchymal stromal cells from JAK2+ myeloproliferative neoplasms: a new therapeutic target?

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