Modulation of Immunoregulatory Properties of Mesenchymal Stromal Cells by Toll-Like Receptors: Potential Applications on GVHD

Sangiorgi, Bruno; Panepucci, Rodrigo Alexandre

doi:10.1155/2016/9434250

Cited by 46 publications

(49 citation statements)

References 96 publications

(172 reference statements)

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“…MSCs also have strong immunomodulation abilities; e.g., they suppress immune cells through the secretion of cytokines, such as prostaglandin E2 (PGE2), indoleamine 2,3 dioxygenase (IDO), hepatocyte growth factor (HGF), and soluble human leukocyte antigen G (sHLA-G) and transform growth factor beta (TGF-b) and interleukin 10 (IL-10) (Budoni et al, 2013;Özdemir et al, 2016). Due to these unique properties, MSCs are clinically used in the treatment of graft versus host disease (GVHD) caused by uncontrolled activation of immune cells (Sangiorgi and Panepucci, 2016) and certain autoimmune diseases, including rheumatoid arthritis (RA), Crohn's disease, and systemic lupus erythematosus (SLE) (Dazzi and Krampera, 2011). However, the clinical responses of patients to MSC treatment are variable, ranging from good responses to only temporary or no effect (Mastri et al, 2014;Silva et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

The investigation of immunomodulatory effects of adipose tissue mesenchymal stem cell educated macrophages on the CD4 T cells

Özdemir¹,

Özdemir²,

Sarıboyacı³

et al. 2019

Immunobiology

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Keywords:Mesenchymal stem cell M1 macrophage M2 macrophage Th1 Th2 Th17 Treg Immunomodulation A B S T R A C T Mesenchymal stem cells (MSCs) are strong immunomodulatory cells investigated in numerous clinical studies on fatal pathologies, such as graft versus host disease and autoimmune diseases; e.g., systemic lupus erythematosus, Crohn's disease, and ulcerative colitis. Macrophages are one of the critical cells linking the innate and adaptive immune system, and it has been shown that MSCs can differentiate between pro-inflammatory M1 phenotype and anti-inflammatory M2 phenotype of macrophages. However, it has not yet been fully clarified whether these differentiated macrophages are functional. In this study, we compared the immunomodulatory effects on the CD4 T cells of M1, M2a and M2c macrophages with the macrophages that directly and indirectly cultured with MSCs. We analyzed the changes in CD14, CD64, CD80, CD163 and CD200R expression to evaluate macrophage phenotypes, and the changes in CD4, IFN-g, IL-4, IL-17a and FoxP3 expression to evaluate T helper subsets using the FACS method. The changes in IL-1b, IL-4, IL-10, IL-12p70, IL-17a and IFN-g in the media supernatants were analyzed using the Luminex method. We also performed WST-1 and Caspase-3 ELISA analyses to observe the proliferation and apoptosis status of the T cells. MSCs were found to differentiate macrophages into a distinctive phenotype, which was close to the M2c phenotype, but was not considered as an M2c cell due to the low expression of CD163, a characteristic marker for M2c. While MEM-D, MEM-ID and MSCs showed similar inhibitory effects on the Th2 and Th17 cells, the most significant increase in Treg cell frequencies was seen in MEM-D cells. Macrophages can alter their phenotypes and functions according to the stimuli from the environment. The fact that macrophages educated with MSCs suppressed the production of all the cytokines we evaluated even after the removal of MSCs suggests that these cells may be differentiated by MSCs into a suppressive macrophage subgroup. However, the Treg cell activation caused by direct interactions between MSCs and macrophage cells may be the most prominent observation of this study compared to previous work. As a result, according to our data, the interactions between MSCs and macrophages may lead to differentiation of macrophage cells into an immunosuppressive phenotype, and these macrophages may suppress the T lymphocyte subgroups at least as effectively as MSCs. However, our data obtained from in vitro experiments should be supported by future in vivo studies.

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Section: Introductionmentioning

confidence: 99%

The investigation of immunomodulatory effects of adipose tissue mesenchymal stem cell educated macrophages on the CD4 T cells

Özdemir¹,

Özdemir²,

Sarıboyacı³

et al. 2019

Immunobiology

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“…The production of these factors by MSCs also relies upon their phenotype, which comes as a result of the interaction between the paracrine factors from their surrounding microenvironment with the receptors presented on MSCs surface, such as Toll-like receptors (TLR) [54]. According to Waterman et al, two different MSC phenotypes can be distinguished: proinflammatory MSC phenotype (MSC1; accomplished by TLR4 interaction with its ligand) and anti-inflammatory MSC phenotype (MSC2; as a result of TLR3 bounding with its ligand) [50].…”

Section: Mscs and Immune Systemmentioning

confidence: 99%

Role of Mesenchymal Stromal Cells as Therapeutic Agents: Potential Mechanisms of Action and Implications in Their Clinical Use

Jimenez-Puerta

Marchal

López‐Ruiz

et al. 2020

JCM

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Due to the great therapeutic interest that involves the translation of mesenchymal stromal cells (MSCs) into clinical practice, they have been widely studied as innovative drugs, in order to treat multiple pathologies. MSC-based cell therapy involves the administration of MSCs either locally or systemically into the receptor body where they can traffic and migrate towards the affected tissue and participate in the process of healing. The therapeutic effects of MSCs compromise of different mechanisms such as the functional integration of differentiated MSCs into diseased host tissue after transplantation, their paracrine support, and their impact on the regulation of both the innate and the acquired immune system. Here, we establish and provide recent advances about the principal mechanisms of action through which MSCs can perform their activity and effect as a therapeutic tool. The purpose of this review is to examine and discuss the MSCs capacity of migration, their paracrine effect, as well as MSC-mediated modifications on immune cell responses.

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“…Consequently, TLRs have been implicated in the pathogenesis of a range of conditions in which such an immune response is dysregulated. This makes them potential therapeutic targets in a variety of diseases, including cardiovascular disorders , inflammatory diseases such as rheumatoid arthritis and SLE , and GvHD . In fact, several agonists of TLR signaling (e.g., Imiquimod, Resiquimod, CpG‐ODN, PIC, and MPLA) have been evaluated in clinical trials for the treatment of various human diseases, including a wide range of malignancies, viral infections, and allergic conditions.…”

Section: Tlr‐mirna Regulatory Axis In Mscs: a Therapeutic Perspectivementioning

confidence: 99%

Concise Review: TLR Pathway-miRNA Interplay in Mesenchymal Stromal Cells: Regulatory Roles and Therapeutic Directions

2018

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Mesenchymal stromal cells (MSCs) deploy Toll-like receptors (TLRs) to respond to exogenous and endogenous signals. Activation of TLR pathways in MSCs alters their inflammatory profile and immunomodulatory effects on cells from both the innate and adaptive immune systems. Micro-RNAs (miRNAs), whose expression is modulated by TLR activation, can regulate inflammatory responses by targeting components of the TLR signaling pathways either in MSCs or in the cells with which they interact. Here, we review how the miRNA-TLR pathway axis can regulate the immunomodulatory functions of MSCs, including their interactions with monocytes/macrophages and natural killer cells, and discuss the therapeutic implications for MSC-based therapies. Stem Cells 2018;36:1655-1662.

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Modulation of Immunoregulatory Properties of Mesenchymal Stromal Cells by Toll-Like Receptors: Potential Applications on GVHD

Cited by 46 publications

References 96 publications

The investigation of immunomodulatory effects of adipose tissue mesenchymal stem cell educated macrophages on the CD4 T cells

The investigation of immunomodulatory effects of adipose tissue mesenchymal stem cell educated macrophages on the CD4 T cells

Role of Mesenchymal Stromal Cells as Therapeutic Agents: Potential Mechanisms of Action and Implications in Their Clinical Use

Concise Review: TLR Pathway-miRNA Interplay in Mesenchymal Stromal Cells: Regulatory Roles and Therapeutic Directions

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