Immunomodulatory Properties of Mesenchymal Stem Cells Combined with Mycophenolate Mofetil Induce T Cell Regulation and Prolong Renal Allografts Survival in Cynomolgus Monkeys

Abstract Abstract 4698 Background: It is important to overcome the limitations such as graft rejection and graft versus host disease (GvHD) in allogeneic hematopoietic stem cell transplantation. Mesenchymal stem cells (MSCs), which evoke only minimal immune reactivity, may have anti-inflammatory and immunomodulatory effects. Purpose: In this study, we aimed to identify the immunomodulatory properties of human MSCs and to elucidate the possible mechanism of their properties for clinical treatment of allogeneic conflicts using MSCs. Materials & Methods: We conducted a comparative analysis about the immunomodulatory properties of MSCs derived from adult human tissues, including bone marrow (BM), adipose tissues (AT), umbilical cord blood (CB), and cord Wharton's jelly (WJ), in vitro and in vivo models. Results: AT-MSCs, CB-MSCs, and WJ-MSCs effectively suppressed phytohemagglutinin (PHA)-induced T-cell proliferation as effectively as did BM-MSCs. Levels of interferon (IFN)-g secreted from activated T-cells increased over time, but these levels were significantly reduced when cocultured with each type of MSCs. In addition, expression of indoleamine 2,3-dioxygenase (IDO) increased in MSCs treated with IFN-γ via JAK/STAT1 signaling pathways. Treatment with anti-IFN-g antibodies, JAK1/2 inhibitor or STAT1 siRNA restored PHA-induced T-cell proliferation. Use of an antagonist, 1-methyl-L-tryptophan, also restored PHA-induced T-cell proliferation, suggesting that IDO contributes to IFN-g-induced immunosuppression in MSCs. Moreover, infusion of IFN-g-treated MSCs decreased symptoms for human peripheral blood-derived mononuclear cells-induced GvHD in NOD/SCID mice, which resulted in an increase of survival rate of in vivo GvHD model. Conclusion: These data indicate that IFN-γ produced by activated T-cells is correlated with induction of IDO expression in MSCs by IFN-γ receptor/JAK/STAT1 pathway, which resulted in suppression of T-cell proliferation. Our findings suggest that MSCs derived from BM, AT, CB, or WJ could be used for clinical treatment of allogeneic conflicts. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Acetylsalicylic acid rescues the immunomodulation of inflamed gingiva-derived mesenchymal stem cells via upregulating FasL in mice

Stem Cell Research & Therapy ◽

10.1186/s13287-019-1485-5 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Tingting Yu ◽

Boxi Yan ◽

Jing Li ◽

Ting Zhang ◽

Ruili Yang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

T Cell ◽

Acetylsalicylic Acid ◽

Cell Apoptosis ◽

Fas Ligand ◽

T Cell Apoptosis ◽

Immunomodulatory Capacity ◽

Immunomodulatory Properties

Abstract Background Gingiva-derived mesenchymal stem cells (GMSCs) obtained multipotent differentiation and immunomodulatory properties. However, collecting healthy gingival tissues may be challenging in the clinical situation. Thus, in our present study, we aim to evaluate whether the immunomodulatory capacity of gingiva-derived mesenchymal stem cells from inflamed gingival tissues (iGMSCs) is impaired and find a way to rescue their deficient properties. Methods We compared the immunomodulation capacity of GMSCs and iGMSCs using an in vitro co-culture system and a mouse colitis model. T cell apoptosis, T helper 17 (Th17), and regulatory T (Treg) cell differentiation were detected by flow cytometry analysis. Results We demonstrated that iGMSCs obtained a decreased immunomodulatory capacity compared with GMSCs. Acetylsalicylic acid (ASA) pretreatment was able to rescue iGMSCs’ impaired immunomodulatory properties. Mechanistically, ASA was capable of upregulating the expression of Fas ligand (FasL) in iGMSCs, leading to an improvement in iGMSC-mediated T cell apoptosis and therapeutic efficacy in the treatment in colitis mice. Conclusions This study indicates that the deficient immunomodulatory function of iGMSCs could be rescued by ASA pretreatment via upregulating of FasL in mice. This strategy might serve as a practical approach to rescue deficient MSC function for further therapeutic application.

Download Full-text

Modulation of Immune Response and T-Cell Regulation by Donor Adipose-Derived Stem Cells in a Rodent Hind-Limb Allotransplant Model

Plastic & Reconstructive Surgery ◽

10.1097/prs.0b013e318230c60b ◽

2011 ◽

Vol 128 (6) ◽

pp. 661e-672e ◽

Cited By ~ 42

Author(s):

Yur-Ren Kuo ◽

Chien-Chang Chen ◽

Shigeru Goto ◽

I-Te Lee ◽

Chong-Wei Huang ◽

...

Keyword(s):

Stem Cells ◽

Immune Response ◽

T Cell ◽

Hind Limb ◽

Adipose Derived Stem Cells ◽

Cell Regulation ◽

T Cell Regulation

Download Full-text

TGF-β2 Reduces the Cell-Mediated Immunogenicity of Equine MHC-Mismatched Bone Marrow-Derived Mesenchymal Stem Cells Without Altering Immunomodulatory Properties

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.628382 ◽

2021 ◽

Vol 9 ◽

Author(s):

Alix K. Berglund ◽

Julie M. Long ◽

James B. Robertson ◽

Lauren V. Schnabel

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Transforming Growth Factor ◽

Mhc Molecules ◽

Immunomodulatory Properties

Allogeneic mesenchymal stem cells (MSCs) are a promising cell therapy for treating numerous diseases, but major histocompatibility complex (MHC)-mismatched MSCs can be rejected by the recipient’s immune system. Pre-treating MSCs with transforming growth factor-β2 (TGF-β2) to downregulate surface expression of MHC molecules may enhance the ability of allogeneic MSCs to evade immune responses. We used lymphocyte proliferation assays and ELISAs to analyze the immunomodulatory potential of TGF-β2-treated equine bone marrow-derived MSCs. T cell activation and cytotoxicity assays were then used to measure the in vitro cell-mediated immunogenicity. Similar to untreated MSCs, TGF-β2-treated MSCs inhibited T cell proliferation and did not stimulate MHC-mismatched T cells to proliferate. Additionally, similar quantities of prostaglandin E2 and TGF-β1 were detected in assays with untreated and TGF-β2-treated MSCs supporting that TGF-β2-treated MSCs retain their strong immunomodulatory properties in vitro. Compared to untreated MSCs, TGF-β2-treated MSCs induced less T cell activation and had reduced cell-mediated cytotoxicity in vitro. These results indicate that treating MSCs with TGF-β2 is a promising strategy to reduce the cell-mediated immunogenicity of MHC-mismatched MSCs and facilitate allogeneic MSC therapy.

Download Full-text

Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells for regenerative therapies

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-0030-1268919 ◽

2011 ◽

Vol 59 (S 01) ◽

Author(s):

M Stubbendorff ◽

T Deuse ◽

K Tang-Quan ◽

H Reichenspurner ◽

RC Robbins ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Immunomodulatory Properties ◽

Regenerative Therapies

Download Full-text

Comparative analysis of the immunomodulatory properties of equine adult-derived mesenchymal stem cells

Cell Medicine ◽

10.3727/215517911x647217 ◽

2012 ◽

Author(s):

Danielle D. Carrade ◽

Michael W. Lame ◽

Michael S. Kent ◽

Kaitlin C. Clark ◽

Naomi J. Walker ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Comparative Analysis ◽

Immunomodulatory Properties

Download Full-text

Mesenchymal stem cells alleviate experimental immune-mediated liver injury via chitinase 3-like protein 1-mediated T cell suppression

Cell Death and Disease ◽

10.1038/s41419-021-03524-y ◽

2021 ◽

Vol 12 (3) ◽

Author(s):

Qiuli Liu ◽

Xiaoyong Chen ◽

Chang Liu ◽

Lijie Pan ◽

Xinmei Kang ◽

...

Keyword(s):

Stem Cells ◽

T Cells ◽

Mesenchymal Stem Cells ◽

T Cell ◽

Liver Injury ◽

T Cell Activation ◽

Gene Set Enrichment Analysis ◽

Human Umbilical Cord ◽

Con A ◽

Immune Mediated

AbstractLiver diseases with different pathogenesis share common pathways of immune-mediated injury. Chitinase-3-like protein 1 (CHI3L1) was induced in both acute and chronic liver injuries, and recent studies reported that it possesses an immunosuppressive ability. CHI3L1 was also expressed in mesenchymal stem cells (MSCs), thus we investigates the role of CHI3L1 in MSC-based therapy for immune-mediated liver injury here. We found that CHI3L1 was highly expressed in human umbilical cord MSCs (hUC-MSCs). Downregulating CHI3L1 mitigated the ability of hUC-MSCs to inhibit T cell activation, proliferation and inflammatory cytokine secretion in vitro. Using Concanavalin A (Con A)-induced liver injury mouse model, we found that silencing CHI3L1 significantly abrogated the hUC-MSCs-mediated alleviation of liver injury, accompanying by weakened suppressive effects on infiltration and activation of hepatic T cells, and secretion of pro-inflammatory cytokines. In addition, recombinant CHI3L1 (rCHI3L1) administration inhibited the proliferation and function of activated T cells, and alleviated the Con A-induced liver injury in mice. Mechanistically, gene set enrichment analysis showed that JAK/STAT signalling pathway was one of the most significantly enriched gene pathways in T cells co-cultured with hUC-MSCs with CHI3L1 knockdown, and further study revealed that CHI3L1 secreted by hUC-MSCs inhibited the STAT1/3 signalling in T cells by upregulating peroxisome proliferator-activated receptor δ (PPARδ). Collectively, our data showed that CHI3L1 was a novel MSC-secreted immunosuppressive factor and provided new insights into therapeutic treatment of immune-mediated liver injury.

Download Full-text