Immunoregulatory properties of mesenchymal stem cells: Micro-RNAs

Immunology Letters 219 (2020) 34–45

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Immunology Letters journal homepage: www.elsevier.com/locate/immlet

Review

Immunoregulatory properties of mesenchymal stem cells: Micro-RNAs Zeinab Rostami

a,b

c

, Mohsen Khorashadizadeh , Mohsen Naseri

d,b,

T

*

a

Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran Department of Immunology, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran Medical Biotechnology (PhD), Department of Medical Biotechnology, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran d Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran b c

A R T I C LE I N FO

A B S T R A C T

Keywords: Mesenchymal stem cell microRNA Immunoregulatory

Mesenchymal stem cells (MSCs) are multipotent cells that are excellent candidates for different cellular therapies due to their physiological properties such as immunoregulatory function. whetheare currently utilized for regenerative medication and treatment of a number of inflammatory illnesses given their ability to considerably impact tissue microenvironments via extracellular vesicles or toll-like receptor pathway modulation. MicroRNAs (miRNAs) are small noncoding RNAs that target the messenger RNA and play a critical role in different biological procedures, such as the development and reaction of the immune system. Moreover, miRNAs have recently been revealed to have serious functions in MSCs to regulate immunomodulatory properties. In this review, we study how the miRNAs pathway can modulate the immunoregulatory activity of MSCs by counting their interactions with immune cells and also discuss the possibility of using miRNA-based implications for MSC-based therapies.

1. Introduction Mesenchymal stem cells (MSCs) as the most important multipotent adult stromal cells can be differentiated into different lines such as osteoblasts, adipose, chondrocytes. Moreover, secretion of growth factors and cytokines with paracrine effects favor the regeneration of damaged tissues [1,2]. MSCs are isolated from various adult tissue sources, including adipose [3], cord blood [4], placenta [5], deciduous teeth [6], dermal tissue [7], synovial fluid [8], and amniotic fluid [9]. MSC surface antigens consist of CD105, CD73, and CD90 [10], but do not have human leukocyte antigen-DR and hematopoietic endothelial markers (CD45, CD34, CD14, CD11b, CD79a or CD19) [11,12]. Primary pre-clinical studies on MSCs have focused on the role of MSCs in tissue regeneration given their capacity to differentiate and migrate to injury sites [11,12]. Moreover, because of the immunomodulatory properties of MSCs, they are effective candidates for therapeutic applications aimed for treatment of immune system diseases [13]. For example, in a Phase III randomized control study, it was indicated that expanded allogeneic hASCs had effective and safe application in the treatment of complex perianal fistulae in Crohn’s disease [14]. The immune modulation of bone marrow mesenchymal stem cells (BMSCs) is characterized to have various mechanisms and, generally, ⁎

has two methods of direct contact between cells and secretion of immune regulatory factors [15,16]. Recently, studies have shown that microRNAs (miRNAs) are involved in the immunomodulatory function of MSCs [17–19]. A miRNA is small, non-coding RNA (20–22 nucleotides) that plays a significant role in the posttranscriptional repression of its target genes by binding to its target messenger RNA (mRNA) [20]. A miRNA often plays a vital role in modification of almost all cellular processes, proliferation, cell growth, and differentiation [21,22]. In addition, several miRNAs have been developed related to normal immune function [23]. Among them are the mir-17/92 cluster, mir-181, and mir-155, which have been shown to be key managers of different immune responses, e.g. T-cell development [24]. In this review, we are studying mechanisms with which MSCs can play a role in the function of immune cells, with particular emphasis on miRNAs. We then discuss current progresses in the miRNA regulation of adaptive and innate immunity, with highlighting mechanisms which are basic for this regulation. We find that miRNAs have great potential in both recognizing the immunomodulatory properties of MSCs and better developing diagnostic and therapeutic strategies. 2. Immunomodulatory properties of MSCs The immunoregulatory activity of MSCs had been underestimated

Corresponding author at: Cellular and molecular research center, Birjand University of medical sciences, Birjand, Iran. E-mail address: [email protected] (M. Naseri).

https://doi.org/10.1016/j.imlet.2019.12.011 Received 16 October 2019; Received in revised form 16 December 2019; Accepted 30 December 2019 Available online 07 January 2020 0165-2478/ © 2019 Published by Elsevier B.V. on behalf of European Federation of Immunological Societies.

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Fig. 1. The regulator components of MSC immunomodulatory properties: NK (natural killer), TGFẞ1 (transforming growth factor beta 1), HLA-G5 (histocompatibility antigen, class I, G), IDO (indoleamine-2,3-dioxygenase), PGE2 (prostaglandin E2), and NO (nitric oxide).

Fig. 2. The MSC immunomodulatory function. MSCs (mesenchymal stem cells), iNOS (inducible NO synthase), NO (nitric oxide), IL-10, HLA-G5 (histocompatibility antigen, class I, G), TGFẞ1 (transforming growth factor beta 1), HGF (hepatocyte growth factor), PGE2 (prostaglandin E2), IDO (indoleamine-2,3-dioxygenase), STAT3 (signal transducer and activator of transcription 3), NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells), T reg (T regulatory), NK (natural killer), DC (dendritic cell), Ab (anti body), and M2 (anti-inflammatory macrophage).

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In addition, HLA-G5 induces the production of IL-10 using a positive loop [53,55].

until 1998 when the immunosuppressive potential of in vitro cultured MSCs was firstly realized [25]. Sufficient evidence indicates the immunoregulatory property of each class of MSCs [26], a combined humoral and cellular effect [15,27,28]. This MSC property has drawn much attention in pre-clinical and clinical research. Studies have shown that MSCs produce large amounts of growth factors, cytokines, and differentiation factors for the regulation of immune reactions and inflammation through modifying PBMCs (peripheral blood mononuclear cells) [15,16,27–29]. Stem cells from diverse origins produce different types and quantities of cytokines, micro-RNA, growth factors, exosomes and chemokines [30–35] (Figs. 1 and 2).

2.2. Immunomodulation of MSCs with cell–cell contact MSCs can decrease the expansion and maturation of immune cells and suppress immune responses. For instance, MSCs can down-regulate T cells and dendritic cell development, decrease B-cell function and expansion, suppress the proliferation and cytotoxicity of NK cells, as well as increase Treg generation via cell-cell contact or soluble mediators [35,56–60]. 2.2.1. T cells T cells have a significant role in the adaptive immune system. MSCs prevent T-cell function and expansion, as well as differentiation of helper T cells [39,61–63]. Moreover, MSCs do not express some of the crucial co-stimulatory molecules, including CD40 or CD40 L, B7-1, and B7-2 and it is assumed that MSC can have a suppressor impact via T-cell anergy stimulation [64,65]. Furthermore, MSCs decrease both pro-inflammatory Th17 and Th1 cell subsets, but increase anti-inflammatory Th2 cell subsets [47]. On the other hand, MSCs prevent the production of IFN - g through Th1 cells and IL-4 through Th2 cells [15,66]. Importantly, the findings of the present study with (CD41, CD25 high foxP3) Treg indicate that MSCs promote differentiation to regulatory T cells as a unique T-cell subgroup that has a suppressing effect on immune responses [47,67]. Moreover, the mesenchymal stem cell can inhibit the formation of Cytotoxic T lymphocyte (CTL) using soluble factors such as TGF-b1, HGF, PGE2 and IDO [15,36,46,68].

2.1. Immunomodulation of MSCs using soluble factors Multi soluble factors have been suggested to interfere with the immunomodulation impact, counting nitric oxide (NO), transforming growth factor-β1 (TGF-β1), prostaglandin E2 (PGE2), hepatocyte growth factor (HGF), indoleamine-2,3-dioxygenase (IDO), and interleukin-10 (IL-10), and histocompatibility antigen, class I, G (HLA-G5) [36–40] In addition, studies have indicated that proinflammatory cytokine interferon-γ (IFN-γ), alone or in blend with tumor necrosis factor-α (TNF-α), IL-1α or IL-1β, induces MSCs to deliver a few soluble factor and compounds consisting of PGE2, cyclooxygenase 2 (COX-2) and IDO that mediate immunosuppressive activity [36–39,41]. 2.1.1. NO NO is one of the central soluble factors renowned to suppress T-cell growth [25,42]. Moreover, investigations have demonstrated that MSCs deliver NO [43]. They have also shown that MSCs can apply regulatory impacts on immune cells through the affected upregulation of inducible NO synthase (iNOS) [39,44].

2.2.2. Dendritic cells DC has a critical role in humoral and cell-mediated immunity [69]. MSCs can inhibit the differentiation, maturation and activation of DCs [52]. Additionally, MSCs can have a downregulating impact on the initial differentiation of monocytes to DCs by decreasing the expression of CD1a, CD86 and Human Leukocyte Antigen – DR (HLA-DR) and also can alter DC maturation by suppressing the expression of CD83 [70]. MSCs can also alter antigen-presenting DCs into anti-inflammatory Tolerogenic DCs. Tolerogenic DCs secrete huge amounts of IL-10 and decrease the ability to stimulate T-cell expansion [52]. Moreover, MSCs are able to decrease the capacity of DCs to secrete IL-12 [70]. MSCs also play an important role in the MSC-mediated downregulation of DC maturation by producing PGE2 and TGF-b1 [46,52,71]. In addition, MSCs can convert cytokine secretion; for example, they can decrease TNF-a of dendritic cell1 (DC1) and increase dendritic cell2 (DC2) and IL-10 secretion [15].

2.1.2. TGFẞ1 and HGF These cytokines can independently decrease alloantigen-activated T lymphocyte proliferation [45,46]. MSCs produce HGF and TGFẞ1, which is elaborated in the MSC intervened generation of (CD4+CD25+Foxp3+) T regulatory (Tregs) and in the reduced proliferation of NK cells [47]. 2.1.3. IDO IDO can down-regulate the proliferation and cytotoxic activity of IL2-induced NK cells in interaction with MSCs [48]. Moreover, IDO is used in the downregulation of the maturation activity of DCs [49]. 2.1.4. PGE2 PGE2 appears to diminish expansion, increase IL-4 and IL-10 secretion, and stimulate CD4+CD25+Foxp3+ and IL-10+IFNү +CD4+Tregs differentiation [50,51]. PGE2 can diminish the separation of monocytes into dendritic cell (DCs) and reduce the cytotoxic and multiplication action of IL-2-initiated NK cells in cooperation with MSCs [52].

2.2.3. NK cells MSCs play a vital role in regulating natural killer (NK) cells [72] by inhibition of the production and expansion of cytokines, cytotoxicity of IL-15 stimulated NK [73], and Reduction of IFN-g production of IL-2stimulated NK [15].

2.1.5. IL-10 IL-10 decreases the production of T helper (Th1) cytokines such as lFNγ, IL-2, and can induce the secretion and expression of HLA-G5, which is another essential molecule in MSC-mediated immunomodulation [53]. It is remarkable in that it expands the immunosuppressive activity of CD4+CD25+ Tregs cocultured with bone marrow MSCs (BMSCs), in view of the high expression of PD-1 on Tregs incited by IL-10 existing in the coculture supernatant [54]. Further, IL10 can decrease the development and capacity of DCs, thereby keeping the limit of DCs to deliver IL12 [54].

2.2.4. B cells MSCs can down regulate effector B cell functions, including immunoglobulin production and plasma cell differentiation [74]. MSCs also reduce the expansion of B cells through cell cycle arrest in the G0/ G1 phase and not via stimulating apoptosis [75]. Moreover, MSCs impact B-cell differentiation by diminishing the production of Immunoglobulin M (IgM), IgG, and IgA [75–78]. In addition, MSCs alter the chemotactic properties of B lymphocytes since they stimulate expression changes in chemokine receptors of B lymphocytes consisting of chemokine receptor type 4 (CXCR4), CXCR5, and chemokine receptor type 7 (CCR7) [75].

2.1.6. HLA-G5 The mesenchymal stem cell expresses the soluble isoform HLA-G5.

2.2.5. MQ Macrophage is another vital immune effector cell [79]. MSCs 36

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[100], mir-146a-5p, etc. [101,102].

repress the stimulation of pro-inflammatory monocytes and macrophages and also improve the conversion of pro-inflammatory M1 macrophages into anti-inflammatory M2 macrophages [80,81], by the downregulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB p65) and the stimulation of STAT3 pathways [82]. This is critical for repairing tissue damage and responding to inflammation [79]. In addition, during the chronic inflammation, extraordinary levels of Th2 cytokines such as IL-4, IL-5, IL-13 induce M2 macrophages, which, in turn, produce IL-6 and IL-10, resulting in alternative licensing of MSCs [83].

3. Biogenesis of miRNAs A miRNA is a type of ∼18–23bp non-coding RNA that regulates gene expression [103,104]. Human miRNAs are contemporary in introns of introns and exons of noncoding transcripts and coding genes [105]. Maximum miRNA biogenesis begins with the processing of primary transcripts using RNA polymerase II/III transcripts co- or posttranscriptionally [106]. Pri-miRNAs consist of 30 poly (A) tails and 7–50 methylguanosine caps [107,108]. The pri- miRNAs are then known and cleaved by the enzymes Drosha and the microprocessor complex subunit DiGeorge syndrome critical region 8 [109,110] to a_70 nt precursor miRNAs or pre-miRNAs as an intermediate with the typical stem-loop hairpin structure in the nucleus. The pre-miRNA is transferred via exportin 5 into the cytoplasm [111,112], where it is cleaved into 22 nt double-stranded miRNA duplexes by the cytoplasmic RNase III enzyme Dicer [106,113]. The mature miRNAs are about 18–25 nucleotides in length, which are loaded onto the Argonaute protein 2, forming a miRNA–protein complex, known as miRNA ribonucleoprotein complex (RISC; RNA-induced silencing complex) [20,114–116].

2.3. Immune regulation activity of MSCs using miRNAs Studies have shown that MSCs can regulate the activity of cells (and perhaps other cells) in the immune system via transferring miRNAs. MSCs transferring miRNAs by secreted exosomes as well as by the extracellular vesicle (EV). In addition, toll-like receptor (TLR) pathways in target immune cells may be regulated by MSCs. [36,84]. 2.3.1. EVs EVs play a significant role in regulating the paracrine mechanism of MSCs, such as immune regulation and tissue repair [85]. EVs are complex membranous structures consisting of mRNAs, functional proteins and miRNAs composing of a lipid bilayer [86]. Therefore, EVs are considered as a physiological extracellular pathway system, through which different cells interact reciprocally through a continuous releaseuptake process [87–90]. The miRNAs profile of EVs forms MSCs consisting of 40 differentially expressed miRNAs, for example, Let-7b [91], mir-223 [92], mir-1180, mir-183, mir-550b, and mir-133a [91]. In addition, recent studies have shown EV-derived miRNAs forms MSCs in the context of immunoregulation of diverse immunosuppressive toward effector cells [93]. For example, mir-223 within EVs from MSCs can have cardio-protective effects [84].

3.1. miRNA gene regulation Each mature miRNA cooperates with a particular mRNA. The constancy of the miRNA-mRNA contact is serious for the operational repression of a potential target [20]. A miRNA binds mostly to the 3′ or 5′ untranslated region (UTR) of its target mRNAs and modulates translational repression as well as mRNA decapping and deadenylation [117,118] [119]. The miRNA binding sites have been recognized in other mRNA regions enclosing the coding sequence, as well as in promoter regions [120]. The binding of miRNAs toward coding regions and 5′ UTR has silencing impact on gene expression [121,122]. However, miRNA interaction with promoter regions has been described to upregulate transcription [123]. A single mRNA may probably be targeted by several diverse miRNAs with mutable competences, and a single miRNA may target more than one mRNA. When miRNA activity is dysregulated, it can extremely change the balance of dynamic biological procedures, such as the immune system development [124–126]. The biogenesis of miRNAs can be managed similar to transcription [127–130], RNA editing [131], Dicer cleavage and microprocessor [132–135], loading onto the localization of action and the RISC complex [136,137].

2.3.2. Modifying TLR signaling MSC: derived miRNAs may regulate TLR pathways in interacting with immune cells [18]. These miRNAs consist of negative modulators for TLR signaling: the miRNAs whose expression is regulated by TLR function and which, subsequently, suppress TLR-mediated responses in MSCs as part of a feedback loop such as mir-155 [94–96], mir-143 [97], mir-23b, etc. [18]; positive modulators for TLR signaling: although most recognized TLR-susceptible miRNAs in MSCs are involved in the negative modulation of TLR pathway, some miRNAs have an improving impact on TLR pathways, possibly through inhibition of molecules with a suppressor effect on signaling such as mir-301a [98,99], mir-21-5p Table 1 Micro-RNA and stem cell immunomodulatory properties. MicroRNA

Target

Cell type

Effect

Ref.

mir-23b mir-494 mir-27b

p50 and p65 COX-2 CXCL12

Downregulation of the NF-κB pathway activation Inhibits PGE2 expression; Inhibits M2 macrophage polarization Augments the inhibitory effect on T-cell proliferation induced by MSCs

[138] [143] [149]

mir-30a

Transforming growth factor-b-activated kinase 1 binding protein 3 (TAB3) TGFBR1 and TGFBRAP1

BMSCs Decidual MSCs adipose-derived MSCs (ASCs) MSCs from human umbilical cords Human umbilical cords and deciduas MSCs UC-MSCs hMSCs Human BM-MSC Wharton’s Jelly (WJ)-MSCs

mir-30a transfection impairs the effect of IL-1b on MSCs (modulating the production of IL-6, COX-2, IL-8 and TNF-a) The blocked activation of the TGF-b signaling pathway

[150]

Increases NFκB activation The Wnt signaling pathway Regulation of NF-κB signaling The NFκB pathway suppresses TLR3-induced IRF3 production

[99] [155] [158] [101,102]

Inhibition of PGE synthase-2 and inhibition of PGE2 release Repressing NOS2 and consequently repressing iNOS expression

[167] [168]

Increasing the differentiation of T cells into Th2 and Treg cells in MSCs; decreasing the differentiation of T cells into Th1 and Th17 cells

[172]

mir-181a miR-301a mir-335 mir-150 mir-146a-5p mir‐146a miR-155

inhibition of NFκB repressing factor(IkB) RUNX2 b-catenin reduction in p65 phosphorylation and blocking IKKε Ptges-2 TAB2

Mir-155

Tbx21, Gata3, Rorc, and Foxp3, resp

BMSCs Bone marrow of tibia and femur MSCs BMSCs

37

[153]

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4. Effect of miRNAs on MSC immunoregulatory activity

4.4. Mir-494

In this review, we describe several studies, listed in Table 1, which indicate the effect of miRNAs on the immunoregulatory properties of MSCs.

Studies have confirmed that the high level of TGF-b3 in preeclampsia (PE) decidua stimulates mir-494 in Decidual MSCs (dMSCs) and consists of an immune imbalance at maternal-fetal interface. In this experiment, it is proved that mir-494 expression is stimulated with TGF-b3. Moreover, it is shown that mir-494-superexpressed dMSCs prevent M2 macrophage polarization, which is intermediated with mir494-reduced PGE2 secretion through (cyclooxygenase-2) COX-2. For the most part, mir-494 diminishes COX-2 at mRNA and protein levels. The reason is that COX-2 is the key molecule in the generation and synthesis of PGE2. Likewise, in this examination, it is demonstrated that macrophages cultured within the sight of MSC-molded medium (CM) have a higher level of CD14+ CD206+ cells than those without CM (2.35 % versus 1.46 %). IL-10 mRNA and protein levels are also shown to substantially increase. However, IL-6 and TNF-a are observed to diminish in macrophages refined with CM at both mRNA and protein levels [143] (Table 1).

4.1. Mir-23 A mir-23b is a complicated device for the induction of Tolerogenic DCs through the culture supernatant (CS) of MSCs. A study conducted in 2015 showed that mir-23b expression was considerably elevated in DCs treated with bone marrow mesenchymal stem cells (BMSCs) CS for 12 h, compared to those treated with CS for 6 h. Likewise, mir-23b expression was upregulated in DCs treated with CS for 24 h compared to those treated for 6 and 12 h. Consequently, mir-23 can increase Tolerogenic DCs in the CS system of MSCs in a time dependent manner [138]. In addition Jingguo et al. acquired similar results that BMSCs downregulated the activation of NF-κB signaling by mir-23b overexpression as well as p50 and p65 level downregulation as a target for mir-23 in the NFκB signaling. This consequently caused a decrease in the differentiation and maturation of DCs in the co-cultural state of BMSCs and DCs [18] (Table 1).

4.5. Mir-let7b Mir-let7b is a miRNA, which plays a role in the immunoregulatory properties of MSCs, since Let‑7b regulates macrophage polarization via the TLR4/NF‑κB/ STAT3/AKT pathway. An experiment conducted in 2015 indicated that EVs derived from LPS-treated (Umbilical cord) UCMSCs improved inflammation and elevated wound healing in a diabetic rat model, which was modulated with let-7b miRNA targeting TLR4 protein. In vitro studies showed that Lipopolysaccharides (LPS) pre-Exo had a better capacity than untreated MSC-determined exosomes (unExo) to control the equalization of macrophages given their increased promotion of M2 macrophage activation and expression of anti-inflammatory cytokines. In addition, the microarray examination of LPS pre-Exo demonstrated the high expression of let-7b [144]. Likewise, the overexpression of let-7b in these cells diminished TLR4 and phosphorylated (p)- p65 proteins while up regulating pSTAT3 and pAkt [145]. Accordingly, this examination demonstrated that mir-let7b (EVs obtained from LPS) treated MSCs by assuming a positive role in regulating the immunoregulatory action of MSCs (Table 1).

4.2. Mir-126 Mir-126a is another miRNAs that has a positive role in the immunoregulatory properties of MSCs through controlling the induction of regulatory T cells. The study conducted by Khosravi et al. (2017) showed that MSC-iTreg (irregular-Treg) generation was directly associated with strong mir-126a in vitro regulations. Therefore, it infused high doses of BMSCs into a murine model of allogeneic skin transplantation and detected that this treatment meaningfully prolonged skin allograft survival compared to phosphate-buffered solution (PBS) treated mice. After splenocytes were collected from grafted mice, it was observed that the Foxp3 gene expression was raised at days 5 and 10 post-graft, only in mice treated with MSCs. These data showed that mir126 through targeting forkhead box P3 (Foxp3) elevated the inducing regulatory T cells and increased the immunomodulatory properties of MSCs [19] (Table 1).

4.6. Mir-21 4.3. Mir-223 Recent experiments on human BMSCs have shown that mir-21 plays a key biological role in recipient cells [146]. Accordingly, mir-21 silences Phosphatase and tensin homolog (PTEN) and plays a critical role in NFŢB activation by promoting c - Jun / AP1 activities that control inflammatory responses [147]. The mir-21 expression in MSC-EXO might be associated with the modulation of immunomodulatory action. The study conducted by Wu et al. (2015) revealed that mir-21 played a critical part in modifying the immunoregulatory properties of BMSCs by decreasing TGF-b1 in experimental colitis in mice and in vitro. Further, it was mechanistically clarified that mir-21 inhibited TGF-b1 expression through targeting phosphatase and tensin homolog deleted from chromosome 10 (PTEN) in BMSCs. It was also observed that mir-21 subsequently promoted the Akt activation then led to the upregulation of the NF-kB pathway [148]. In another investigation, it was indicated that the improving impact of mir-21 on TLR signaling was interceded by negative modulation of Wnt. As a result of LPS incitement, the upregulated mir-21-5p diminished TLR4 and the downstream cytokine (IL-6, IL-1β) gene expression in BM-MSCs. Moreover, mir-21 suppression up-regulated Wnt transcription [100] these experiments were concordant with others and showed that mir-21 played a significant role in the immunoregulatory function of MSC. (Table 1).

Today, studies have shown that mir-223 has a high level of MSCderived exosomes [139,140]. Exosomal mir-223 has an important impact on mesenchymal stem cell immune system regulation. The study conducted by Wang et al. showed that tibia and femoral marrow compartments Mouse MSCs were found to have a cardio-protective impact on sepsis with mir-223 by targeting Semaphorin (Sema3A) and Stat3. In addition, WT-exosomes encased the upper amount of mir-223, which can be carried to cardiomyocytes and thus reduce Sema3A and Stat3 while resulting in elevated cell death and inflammation in cardiomyocytes. Interestingly, the treatment of CLP mice by means of exosomes discharged from mir-223-KO MSCs fundamentally exasperates sepsis-initiated harm because it is perceived that mir-223-KO exosomes include more increased level of Semaphorin 3A (Sema3A) and Stat3 [84]. Sema3A is elevated via Toll-like receptors (TLR) engagement and, when linked to its receptor, Plexin-A4 excites Rac1, JNK and NFκB while aggravating the TLR-mediated cytokine pathway [141]. In addition, in macrophages, ligand incitement of TLR 3 and 4 inhibits mir-223 and raises STAT3, which is an immediate target of mir223 leading to elevated secretion of inflammatory cytokines (IL-6 and IL-1β) [142]. Consequently, these outcomes show that the relationship between MSC-miRNAs and TLR signaling may likewise be interceded in vivo through the intermediate molecules STAT3 and Sema3A, which act as intersection hubs to mediate and/or enhance the TLR-intervened response (Table 1).

4.7. Mir-27 Recent studies have indicated the significant role of miRNAs in 38

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RUNX Family Transcription Factor 2 (RUNX2) was a direct target of mir-335 in bone marrow, adipose tissue and articular cartilage isolated MSCs. The canonical Wnt pathway as a positive MSC self-restoration modulator has also been shown to increase the expression of mir-335 in hMSCs and to be repressed by interferon-c (IFN-c) as a pro-inflammatory cytokine that plays an important role in initiating the immunoregulatory action of hMSCs [155] These studies assessed the immunoregulatory activity of hMSCs using coculture assays and then assessed the potential of hMSCs to inhibit the proliferation of human peripheral blood mononuclear cells (PBMCs) stimulated by PHA.. (Table 1). 4.12-Mir-548: A recent study has shown that mir-548 plays a role in regulating the immunoregulatory properties of MSCs through modulating the NF-κB pathway. The study conducted by Yan et al. showed that MSC transplantation downregulated the NF-ŢB signaling and decreased miRNA-548e (mir-548e) levels in the joint tissue of CIA–mice. This demonstrates that Bone-marrow derived MSCs can similarly decrease inflammation through the miRNA modulation of NFκB in no immune cells and in the absence of a full immune repertoire. This is because mir-548e directly targets IκB, the NFκB suppressor, resulting in NFκB stimulation and inflammatory response initiation. Additionally, MSCs may suppress mir-548e in synovial fibroblasts through the transforming growth factor β (TGFβ) receptor signaling. Since TGFβ is a notable growth factor produced and secreted by MSCs, and since TGFβ levels are essentially expanded in CIA-mouse joints after MSC transplantation, we conjecture that MSCs can suppress mir-548e levels in synovial fibroblasts through TGFβ receptor signaling. TGFβ 1 expands cytoplasmic Iκ B protein levels, but diminishes nuclear NF-κ B protein levels. This suggests that MSCs may hinder mir-548e in synovial fibroblasts through the TGFβ receptor pathway [156] (Table 1).

regulating the immunosuppressive properties of MSCs. For example, mir-27b knockdown by increasing the effect on the CXCL12 production results in the enhanced suppressor effect on Tcell proliferation induced via adipose-derived mesenchymal stem cells(Ad-MSCs) [149]. 4.8. Mir-30 In the study conducted by Hu et al., it was indicated that the incretion of mir-30a reduced the immunosuppressive properties of human umbilical cords MSCs. As a result, IL-1b-pretreated MSCs had significantly inhibited the production of IL-6, COX-2, IL-8 and TNF-a, while mir-30a transfection impaired the impact of IL-1b on MSCs by targeting transforming growth factor-b-activated kinase 1 binding protein 3 (TAB3). Likewise, the over-expression of mir-30a eliminated the anti-inflammatory impact of MSCs on macrophages. In addition to mir-30a transfection, the listing of MSCs was suppressed on (CD4+CD25+Foxp3+) Treg cells [150] therefore this study reveal that mir-30a decreases immunosuppressive activities of IL-1b-elicited mesenchymal stem cells through targeting TAB3. 4.9. Mir-143 Mir-143 diminishes the immunosuppressive activity of MSCs as a negative modulator in the MSC TLR-mediated pathway. Because of human umbilical cord (UC)-MSCs, TLR3 ligand (poly I:C) considerably augments the production of cytokines and chemokines, including IL-6, IL-8, COX-2, IDO, and PGE2, which are associated with the discretion of mir-143 in UC-MSCs. In addition poly(I:C) could enhance MSCs’ antiinflammatory effect on macrophages [97] (Table 1). 4.10. Mir-181a

4.11. Mir-let7a Mir-181a is a vital regulator in the immune system. Experiments demonstrate that mir-181 has a vital role in the development, function, and differentiation of T lymphocytes, B lymphocytes, and NK cells [151,152]. Likewise, another analysis has shown that mir-181a diminishes the activity of Human umbilical cords MSCs to decrease T cell expansion both in vitro and in vivo. In this investigation, it is shown that Mir-181a manages the MSC immunosuppressive property through the MAPK pathway. Furthermore, MSC transfection through mir-181a oligo rises the expression of IL-6, indoleamine 2,3-dioxygenase and Vascular endothelial growth factor (VEGF) via p38 and c-Jun N-terminal kinases (JNK) stimulation. On the other hand, it is indicated that mir-181a regulates the proliferation of MSCs through TGF-b signaling. As a result of the height of mir-181a, the activity of TGF-b pathway declines and the target gene (TGFBR1 and TGFBRAP1) mRNA and protein expression diminish. Moreover, reporter genes through putative mir-181a binding sites from the TGFBR1 and Transforming Growth Factor Beta Receptor Associated Protein 1 (TGFBRAP1) 3-untranslated areas (3-UTRs) diminish within the sight of mir-181a, suggesting that mir-181a binds to TGFBR1 and TGFBRAP1 3-UTRs [153] (Table 1). 4.10-Mir-301: The elevation of mir-301a modifies the secretion or expression of IL-6, IL-8, COX-2, PGE2, and IFN-β and also strongly stimulates IDO expression using umbilical cord (UC-MSCs). Similar to the stimulating impact of UC-MSCs, mir-301a elevates NFκB function and inflammatory gene expression in TLR 3-, 4-, and 9-activated macrophages, which are mediated through suppression of the NFκB inhibitory factor [99] (Table 1). 4.11-Mir-335: Mir-335 plays a pivotal role in modulating the immunoregulation properties of MSCs, indicating the overexpression of mir-335 and the immobilized immunoregulatory property of Bone marrow-derived hMSCs in a murine endotoxemia model. These impacts are accompanied with a severely decreased cell migration potential in response to proinflammatory pathways and the marked inhibition of protein kinase D1 phosphorylation, leading to a pronounced reduction in Activator protein 1 (AP-1) action [154]. One study indicated that

In contrast to mir-let7b, experimental data have shown that mirlet7a plays a negative role in modulating the immunoregulatory properties of MSCs by targeting the 30 UTRs of Fas and FasL mRNA. Accordingly, a study conducted in 2016 showed that suppression of let7a elevated Fas and FasL protein levels in Bone marrow-derived MSCs (Fas attracted T cell migration and FasL stimulated T cell apoptosis). The suppression of let-7a with MSCs was more effective in reducing mortality, inhibiting weight loss, destroying inflammation response and improving the tissue lesion in the graft-versus-host disease Graft versus host disease (GVHD) and the colitis model [157] (Table 1). 4.12. Mir-150-3p Mir-150 is another miRNA that has a role in the immunoregulatory activity of MSCs. A study indicated that mir-150-3p expression increased through TNF-a using the IκB kinase (IKK-dependent) NF-kB pathway in BM-MSC. There are three putative NF-kB binding sites in the promoter region of mir-150, which recognized 2686 regions as major NF-kB binding sites for the stimulation of mir-150 expression using TNF-a and, in turn, targeted β-catenin [158]. Nevertheless, the Wnt/β-catenin signal is involved in inflammatory responses through the interaction of molecules in the TLR pathway containing NFκB [159,160]. Thus, the TLR-mediated response varies in a modulatory loop following TLR function. Subsequently, it is suggested that mir-1503p integrates the inflammation pathway and modulates the immunoregulatory activity of MSCs (Table 1). 4.13. Mir-146 As shown in recent studies, mir-146a is enormously expressed in various types of adult stem cells. When MSCs move to the inflammatory microenvironment in harmed tissues, they have a “short-term memory” for danger signals and display enhanced therapeutic immunoregulation 39

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By Targeting PRKACB Enhances Fas and FasL proteins The TLR4/NF-κB/ STAT3/AKT regulatory signaling pathway Effects of TLR3-activated MSCs Regulation of IκB expression Downregulation of IRAK1, TRAF6, NF-kB, IL-6, and MIP-2 gene expression Targeting IRAK1, TRAF6 and IRF5 in immune cells Human/ Synovial Fluid-Derived MSCs Mice models/(BMSCs) Human/UC-MSCs Human/UC-MSCs Mice models/Bone-marrow derived MSCs Murine models/Bone-marrow derived MSCs Human/UC-MSCs Arthritis Inflammatory diseases (GVHD) Alleviated inflammation and enhanced diabetic cutaneous wound healing sepsis rheumatoid arthritis Diabetic Wound-Healing inflammatory disorders (Sepsis) mir-23b Let-7a let‑7b mir-143 mir-548 mir-146a mir-146a

Experimental data have shown that BMSC-regulated immunosuppression is performed through targeting Table 2 (encoding TGF-β-activated kinase 1 and MAP3K7-binding protein 2) and suppressed Nitric Oxide Synthase 2 (NOS2) and subsequently decreased Inducible nitric oxide synthase (iNOS) expression (encoding NO synthase) [168]. Table 2 and Table 1 are two connector molecules in TLR signaling, which are used via TRAF6 to activate TAK1 as well as the transcription factors NFκB and activator protein 1 [94]. In addition, previous research has shown that the conditioning of MSCs by IFN-γ or a mix of IFN-γ and TNF-α or IL-1β increases mir-155 [94,168]. The expression of mir-155 in MSCs, DC cells, macrophages, and NK cells leads to disabled immunosuppression, DC apoptosis and an expansion in the quantity of proinflammatory cytokines [169–171]. In contrast, another investigation conducted in 2018 indicated that the percentage of CD4+ FOXP3+Treg cells in spleen mononuclear cells (SMCs) cocultured with mir-155-sppressor-transfected MSCs was seriously lower compared with that noted in the control group (P < 0.001). Mir-155-mimics-transfected MSCs repressed the expression of T-box transcription (Tbx21) as a Th1 cell-specific transcription factor, Rorc as a Th17 cell-specific transcription factor, and Suppressor of cytokine signaling 1 (SOCS1), while the expression of GATA Binding Protein 3 (Gata3) and Foxp3 was augmented. Moreover, mir-155-suppresor-transfected BMSCs led to an increase in expression levels of Tbx21, RAR-related orphan receptor C (Rorc) and SOCS1 (the mir-155 target gene) as well as to the inhibition of Gata3 as a Th2 cell-specific transcription factor and Foxp3 as a Treg cell-specific transcription

Disorder

Table 2 The role of micro-RNA regulation in stem cells for the treatment of various diseases.

4.14. Mir-155

mir

Species

Mechanism

Ref.

efficacy by inducing stimulus-responsive modulatory molecules such as mir-146a [96]. Moreover, microarray investigations have demonstrated that MSC-derived EVs have a greater level of miRNAs as compared to MSCs. Moreover, the presence of miRNA-146 in MSC-derived EVs reflects its potential role in their immunoregulatory property [161,162]. Furthermore, it is realized that inflammatory priming induces an increase in miRNA-146 level [163,164]. One study demonstrated that mir-146a-5p suppression in Wharton’s Jelly (WJ)-MSCs was attributed to a significant decrease in p65 phosphorylation in the NFκB signaling (136). The direct aim of mir-146a-5p in WJ-MSCs is to decrease IKKε, which is known to repress TLR3-induced Interferon regulatory factor 3 (IRF3) production via suppressing IKKε, a non-canonical NFκB stimulator [102]. Moreover, Xu et al. (2012) in their study showed that the treatment of diabetic murine wounds with bone marrows MSCs could elevate curative efficacy. Furthermore, this examination demonstrated that mir-146a expression diminished in diabetic mouse wounds, and that the treatment of diabetic wound-healing damage caused by MSC treatment was associated with a significantly increased expression of miR-146a and a related decrease of its objective pro-inflammatory gene expression such as NFkB, Interleukin 1 Receptor Associated Kinase 1 (IRAK1), IL-6, TNF receptor associated factor (TRAF6), and macrophage inflammatory protein 2 (MIP-2) [165]. Moreover, another study showed that pretreatment with IL‐1β could partially enhance the immunomodulatory properties of BMSCs via the exosome‐intervened transfer of mir‐146a in septic mice. The reason is that transferring exosomal mir‐146a to macrophages leads to M2 polarization, and subsequently, to expanded survival in septic mice [166]. In contrast, the study conducted by Matysiak et al. (2013) indicated an increased expression of mir-146a in BMSCs with the suppression of PGE synthase-2 and depression of PGE2 release. On the other hand, it was demonstrated that the suppression of mir-146a re-initiated PGE2 synthesis. Since it was indicated in this study that Prostaglandin E Synthase 2 (Ptges-2) was straightly targeted through mir-146a using a luciferase reporter test, the knockdown of mir-146a with a selective antagomir returned the immunomodulatory function of nBMSCs [167] (Table 1).

[174] [157] [144] [97] [156] [165] [166]

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may be an interesting topic in therapeutic strategies. In this review, we describe several examples of such studies, as presented in section4 and Table 2. Such studies indicate that in the near future, this method can be used to treat different diseases. For instants the Study of X. Yan and his colleagues in 2016 showed that mesenchymal stem cell transplantation (MSC) decreases the frequency of collagen-induced arthritis (CIA) in mice, which is a template for rheumatoid arthritis (RA) in humans by NF-κB signaling activities and decreased levels of miRNA548e (mir-548e) in the joint tissue of CIA-mice [156]. Increasing the immunoregulatory activity of MScs through pretreatment with pro-inflammatory cytokines is an advancing research area. In the 2017 analysis, Y. Song and his colleagues suggested that IL1β pretreatment successfully improved the immunomodulatory abilities of MSCs by exosome-mediated transfer of mir-146a. This research has revealed that MSCs have a therapeutic effects of cecal ligation and puncture (CLP) by more active inducing macrophage polarization to the anti-inflammatory M2 phenotype by paracrine activity [166]. The 2014 study showed that the treatment of osteoarthritis (OA) and rheumatoid arthritis (RA) patients with autologous transplantation of differentiated MSCs had several beneficial effects on cartilage regeneration, including immunoregulatory function, through the incretion of mir-23b Targeting protein kinase cAMP-activated catalytic subunit beta (PRKACB) [174]. In addition, another study indicated that LPS-preconditioned MSC-derived exosomes have a higher potential than untreated MSC-derived exosomes to increase regulatory capabilities for macrophage polarization and chronic inflammation treatment via shuttling let-7b, and these exosomes have a high immunotherapy potential for diabetic cutaneous wound healing [144].

factor. mir-155 favors the classification of T cells into Th2 and Treg cells in BMSCs. However, it inhibits the classification of T cells into Th1 and Th17 cells. This proves that mir-155 expression plays a positive role in the regulation of immunoregulation properties of BMSCs [172]. Instead, the appearance of cytokines and miRNAs in graft infiltrating lymphocytes in the intravenous (IV) and intrathymic (IT) injection of mesenchymal stem cells showed that the IT/IV injection of BMSCs reduced the level of interleukin (IL)-2 and interferon-gamma, but augmented the level of IL-4 and IL-10 in the allogeneic group. Essentially, the IT/IV injection of BMSCs was the greatest approach to elevate the percentage of CD4þ, CD25þ, and Foxp3þ T-cell peripheral blood. Consequently, this outcome shows that the IT/IV injection of BMSCs can decrease mir-155 expression, an alteration in the Th1/Th2 balance, and increase the expression of Treg cells [173]. In addition, the study conducted by Yi-Chun Kuo et al. (2013) showed that extreme stretch augmented the secretion of inflammatory cytokines counting IL8 because of a raised microRNA-155 (mir-155) expression. This initiated the inhibition of Src homology 2 domain–containing inositol 5phosphatase 1 (SHIP1) creation and the consequent initiation of the JNK pathway. The coculture with BMSCs reversed the stretch-stimulated inflammatory reaction as a result of IL-10 production via hMSCs to decrease mir-155 expression in human bronchial epithelial cells (hBECs) [173] (Fig. 3) (Table 1).

5. Therapeutic potential of miRNAs in MSC-based strategies The MSC-based strategy is an interesting method for medications of many disorders due to the immunoregulatory properties of MSCs. In addition, up-regulating MSC therapeutic effect with miRNA regulation

Fig. 3. The role of mir in the immune regulation activity of MSCs. MSCs)mesenchymal stem cells), mir (micro-RNA), TAB3 (TGF-beta activated kinase 1 (MAP3K7) binding protein 3), PTEN (prime time entertainment network), Sema3A (semaphorin-3A), Stat3 (signal transducer and activator of transcription 3), IκB (NFκB inhibitor), CXCL12 (C-X-C motif chemokine 12), FasL (Fas ligand), Tbx21 (T-box transcription factor), Gata3 (GATA binding protein 3), Rorc (nuclear receptor ROR), Foxp3 (forkhead box P3), TAK1 (transforming growth factor beta-activated kinase 1), COX-2 (cyclooxygenase-2), TGFBR1 (TGF beta superfamily of signaling ligands), TGFBRAP1 (transforming growth factor, beta receptor associated protein 1), AKT (protein Kinase B), Ptges-2 (prostaglandin E synthase 2), IKKε (IκB kinases), PGE2 (prostaglandin E2), TNF-a (tumor necrosis factor-α), NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells), AP-1(activator protein 1), TLR (toll like receptor), Th (T helper), Treg (T regulatory), and M2 (anti-inflammatory macrophage). 41

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6. Concluding remarks

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MSCs are good candidates for cellular therapy, which may modulate the current pharmaceutical landscape. Studies have revealed that MSCs have immunoregulatory properties, and the comprehension of the basic mechanisms of these properties will be the key to use MSC-based therapies in therapeutic applications. In this approach, the discovery of strategies to increase the power of MSCs is an active area of the clinical research. Recent experiments have indicated that MSCs can regulate immune cell capacity with miRNAs [143,175], such as T cells expansion and differentiation and macrophage proliferation. Additionally, many inflammatory and immune illnesses, such as graft-versus-host disease (GVHD), systemic lupus erythematosus and multiple sclerosis (MS), can be cured with MSC approaches [176] based on the target modulatory impact of miRNA on immunomodulatory properties of MSCs. Investigation of miRNAs helps the comprehension of their effects at pathophysiological level and the advancement of procedures to regulate their expression in MSCs. Moreover, studies consider that miRNA can influence different pathways by targeting several genes. Deregulated miRNAs can be similarly used as biomarkers of key pathological features. For example, responses to treatments and deregulated miRNAs can be similarly used as biomarkers for detecting key pathological features [177–180]. Studies have revealed that MSC treatment appears to be well-tolerated and have good protective outcomes. [181]. However, we need controlled long-term studies to confirm whether this new MSC-based therapy is appropriate. In this review, we expressed the role of microRNAs in the immunoregulatory activity of MSCs and their mechanisms as well as therapeutic applications of these approaches. Author’s contributions Zeinab Rostami: Drafting of the manuscript. Dr. Mohsen Khorashadizade: Critical revision of the manuscript for important intellectual content. Dr. Mohsen Naseri: Obtaining of funding, conception, design and supervision. Funding This work was supported by the Medical research Council of Birjand University of Medical Sciences. Declaration of Competing Interest The authors declare no conflict of interest. Acknowledgments The authors would like to thank the staff at the Central Research Lab of Birjand University of Medical Sciences for their help and cooperation. References [1] S. Ma, N. Xie, W. Li, B. Yuan, Y. Shi, Y. Wang, Immunobiology of mesenchymal stem cells, Cell Death Differ. 21 (2) (2014) 216. [2] D.G. Phinney, D.J. Prockop, Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair—current views, Stem Cells 25 (11) (2007) 2896–2902. [3] T. Alstrup, M. Eijken, A.B. Bohn, B. Møller, T.E. Damsgaard, Isolation of adipose tissue–derived stem cells: enzymatic digestion in combination with mechanical distortion to increase adipose tissue–derived stem cell yield from human aspirated fat, Curr. Protoc. Stem Cell Biol. 48 (1) (2019) e68. [4] K. Bieback, P. Netsch, Isolation, culture, and characterization of human umbilical cord blood-derived mesenchymal stromal cells, Mesenchymal Stem Cells, Springer, 2016, pp. 245–258.

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