Mesenchymal stem cells promote macrophage polarization toward M2b-like cells

Kudlik, Gyöngyi; Hegyi, Beáta; Czibula, Ágnes; Monostori, Éva; Buday, László; Uher, Ferenc

doi:10.1016/j.yexcr.2016.08.022

Cited by 35 publications

(28 citation statements)

References 52 publications

(72 reference statements)

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“…Nevertheless, our data with recombinant IL-6 implicate that additional MSC-derived soluble factors might also be involved in M2b polarization. In contrast to previously published work [ 31 , 43 ], PGE2 was not found to influence macrophage polarization or to favor M2b polarization. COX-2 knockdown indeed strongly reduced PGE2 secretion, without affecting NO or IL-6 secretion by preconditioned MSCs, but this impaired PGE2 production did not diminish the expression of M2 marker genes, except for FIZZ/RELMα .…”

Section: Discussioncontrasting

confidence: 99%

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Preconditioning of bone marrow-derived mesenchymal stem cells highly strengthens their potential to promote IL-6-dependent M2b polarization

et al. 2018

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BackgroundDuring the last decade, mesenchymal stem cells (MSCs) have gained much attention in the field of regenerative medicine due to their capacity to differentiate into different cell types and to promote immunosuppressive effects. However, the underlying mechanism of MSC-mediated immunoregulation is not fully understood so far. Macrophages are distinguished in classical activated, pro-inflammatory M1 and alternatively activated M2 cells, which possess different functions and transcriptional profiles with respect to inflammatory responses. As polarization is not fixed, macrophage functional plasticity might be modulated by the microenvironment allowing them to rapidly react to danger signals and maintaining tissue homeostasis.MethodsMurine MSCs were preconditioned with IL-1ß and IFN-ɣ to enhance their immunosuppressive capacity regarding macrophage polarization under M1- and M2a-polarizing conditions. Macrophage polarization was analyzed by real-time PCR, flow cytometry, and cytokine detection in culture supernatants. The role of MSC-derived nitric oxide (NO), prostaglandin E2 (PGE2), and IL-6 in this process has been evaluated using siRNA transfection and IL-6 receptor-deficient macrophages, respectively.ResultsPreconditioned, but not unprimed, MSCs secreted high levels of NO, IL-6, and PGE2. Co-culture with macrophages (M0) in the presence of M1 inducers (LPS + IFN-ɣ) led to significant reduction of CD86 and iNOS protein in macrophages and diminished TNF-α secretion. Additionally, CD86 and iNOS protein expression as well as NO and IL-10 secretion were markedly increased under M2a-polarizing culture conditions (IL-4). MSC-dependent macrophage polarization did not depend on direct cell-cell contact. Co-culturing in the presence of LPS and IFN-ɣ resulted in the upregulation of M2a, M2b, and M2c marker genes, whereas in the presence of IL-4 only M2b markers were significantly increased. In turn, IL-10-producing regulatory M2b cells significantly inhibited IFN-ɣ expression in CD4+ T lymphocytes. Finally, we show that MSC-mediated macrophage polarization strongly depends on IL-6, whereas a minor role for NO and PGE2 was found.ConclusionsPreconditioning of MSCs highly strengthens their capacity to regulate macrophage features and to promote immunosuppression. Repression of M1 polarization during inflammation and M2b polarization under anti-inflammatory conditions strongly depend on functional IL-6 signaling in macrophages. The potential benefit of preconditioned MSCs and IL-6 should be considered for future clinical treatment.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-1039-2) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 99%

“…Previous studies argue for a prominent role of PGE2 as a key immunosuppressive mediator derived from MSCs [ 36 , 41 , 43 ]. Additionally, both PGE2 and NO production are positively regulated by IL-6 and their secretion is strongly reduced in the absence of IL-6.…”

Section: Discussionmentioning

confidence: 99%

Preconditioning of bone marrow-derived mesenchymal stem cells highly strengthens their potential to promote IL-6-dependent M2b polarization

et al. 2018

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“…Immunomodulatory properties of MSCs has confirmed in the different studies, demonstrating the role of MSCs in migration, survival and functional repolarization of neutrophils, macrophages, mast cells, natural killer (NK) cells, dendritic cells, and lymphocyte subsets [Cassatella et al, ; Brown et al, ; Cho et al, ; Le Blanc and Davies, ]. Furthermore, numerous studies have shown that MSCs could promote macrophage polarization toward regulatory or M2b‐like profile [Maggini et al, ; Abumaree et al, ; Kudlik et al, ]. Recently, Kudlik et al [] have reported that PGE‐2 plays a pivotal role in MSC‐modified Mϕ polarization toward a more M2b‐like, IL‐10‐dominant immunosuppressive phenotype.…”

Section: Discussionmentioning

confidence: 98%

“…Furthermore, numerous studies have shown that MSCs could promote macrophage polarization toward regulatory or M2b‐like profile [Maggini et al, ; Abumaree et al, ; Kudlik et al, ]. Recently, Kudlik et al [] have reported that PGE‐2 plays a pivotal role in MSC‐modified Mϕ polarization toward a more M2b‐like, IL‐10‐dominant immunosuppressive phenotype.…”

Section: Discussionmentioning

confidence: 99%

Pretreatment of Mesenchymal Stem Cells WithLeishmania majorSoluble Antigens Induce Anti-Inflammatory Properties in Mouse Peritoneal Macrophages

et al. 2017

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Recent studies have demonstrated the influential role of microbial stimulus in characteristics and immunomodulatory effects of mesenchymal stem cells (MSCs). Due to the migration of MSCs to infection site, it is of importance to understand the interaction of microbial ligands with MSCs in order to clarify the positive or negative role of MSCs in the control of infection. In this research, we assess leishmanial soluble antigen (LSA)-primed MSCs on macrophage immune responses to lipopolysaccharide (LPS). For this purpose, the effects of both conditioned media (CM) and cell-cell contact of LSA primed MSCs were determined on macrophage responses to LPS. According to the obtained results, MSC-treated macrophages demonstrated an alternatively activated macrophages with higher levels of interleukin-10 (IL-10) and transforming growth factor-alpha (TNF-α) and lower levels of IL-6 and nitric oxide (NO) production as compared to the controls. In addition, phagocytosis of apoptotic thymocytes was induced in MSC-treated macrophages. In conclusion, it seems that MSCs trigger an anti-inflammatory phenotype in macrophages at Leishmania infected sites in order to enhance the induction of immune regulatory cells and clearance of apoptotic cells. J. Cell. Biochem. 118: 2764-2779, 2017. © 2017 Wiley Periodicals, Inc.

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“…MSCs actively influence the function of macrophages by influencing their polarization status ( Figure 4 ) [ 57 ]. For example, MSCs shift the polarization of macrophages from a TNF α -secreting M1 signature to an immunosuppressive IL-10-expressing phenotype which may be mediated through a prostaglandin- (PGE-) 2-based mechanism [ 58 ]. Wolfe et al also demonstrated that conditioned media collected from MSCs were able to induce an M2 phenotype in macrophages indicative of an upregulation of arginase 1 and CD206 [ 59 ].…”

Section: The Interaction Of Mscs and The Immune System In The Tumomentioning

confidence: 99%

The Immunomodulatory Effects of Mesenchymal Stem Cell Polarization within the Tumor Microenvironment Niche

Rivera-Cruz

Shearer

Neto

et al. 2017

Stem Cells International

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Mesenchymal stem cells (MSCs) represent a promising tool for cell therapy, particularly for their antitumor effects. This cell population can be isolated from multiple tissue sources and also display an innate ability to home to areas of inflammation, such as tumors. Upon entry into the tumor microenvironment niche, MSCs promote or inhibit tumor progression by various mechanisms, largely through the release of soluble factors. These factors can be immunomodulatory by activating or inhibiting both the adaptive and innate immune responses. The mechanisms by which MSCs modulate the immune response are not well understood. Because of this, the relationship between MSCs and immune cells within the tumor microenvironment niche continues to be an active area of research in order to help explain the apparent contradictory findings currently available in the literature. The ongoing research aims to enhance the potential of MSCs in future therapeutic applications.

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Mesenchymal stem cells promote macrophage polarization toward M2b-like cells

Cited by 35 publications

References 52 publications

Preconditioning of bone marrow-derived mesenchymal stem cells highly strengthens their potential to promote IL-6-dependent M2b polarization

Preconditioning of bone marrow-derived mesenchymal stem cells highly strengthens their potential to promote IL-6-dependent M2b polarization

Pretreatment of Mesenchymal Stem Cells WithLeishmania majorSoluble Antigens Induce Anti-Inflammatory Properties in Mouse Peritoneal Macrophages

The Immunomodulatory Effects of Mesenchymal Stem Cell Polarization within the Tumor Microenvironment Niche

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