Mesenchymal Stem and Stromal Cells Harness Macrophage-Derived Amphiregulin to Maintain Tissue Homeostasis

Ko, Jung Hwa; Kim, Hyeon Ji; Jeong, Hyun Jeong; Lee, Hyun Ju; Oh, Joo Youn

doi:10.1016/j.celrep.2020.02.062

Cited by 92 publications

(81 citation statements)

References 72 publications

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“…AREG or amphiregulin is an Epidermal Growth Factor (EGF)-like molecule that has recently been shown to play a central role in orchestrating both host resistance to pathogens and immune tolerance mechanisms [ 46 , 47 , 48 ]. This cross-talk between immune cells (such as macrophages) and epithelial cells are programmed to promote inflammation resolution and tissue regeneration, leading to homeostasis after injury [ 49 ]. However, with a chronic persistent inflammatory stimulus such as cigarette smoking, it could promote proliferation of structural cells such as fibroblasts and their production of pro-inflammatory cytokines such as IL-8, vascular endothelial growth factor (VEGF), and transforming growth factor alpha (TGF-α) with augmented expression in chronic inflammatory conditions such as rheumatoid arthritis [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Abundance of Non-Polarized Lung Macrophages with Poor Phagocytic Function in Chronic Obstructive Pulmonary Disease (COPD)

et al. 2020

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Lung macrophages are the key immune effector cells in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Several studies have shown an increase in their numbers in bronchoalveolar lavage fluid (BAL) of subjects with COPD compared to controls, suggesting a pathogenic role in disease initiation and progression. Although reduced lung macrophage phagocytic ability has been previously shown in COPD, the relationship between lung macrophages’ phenotypic characteristics and functional properties in COPD is still unclear. (1) Methods: Macrophages harvested from bronchoalveolar lavage (BAL) fluid of subjects with and without COPD (GOLD grades, I–III) were immuno-phenotyped, and their function and gene expression profiles were assessed using targeted assays. (2) Results: BAL macrophages from 18 COPD and 10 (non-COPD) control subjects were evaluated. The majority of macrophages from COPD subjects were non-polarized (negative for both M1 and M2 markers; 77.9%) in contrast to controls (23.9%; p < 0.001). The percentages of these non-polarized macrophages strongly correlated with the severity of COPD (p = 0.006) and current smoking status (p = 0.008). Non-polarized macrophages demonstrated poor phagocytic function in both the control (p = 0.02) and COPD (p < 0.001) subjects. Non-polarized macrophages demonstrated impaired ability to phagocytose Staphylococcus aureus (p < 0.001). They also demonstrated reduced gene expression for CD163, CD40, CCL13 and C1QA&B, which are involved in pathogen recognition and processing and showed an increased gene expression for CXCR4, RAF1, amphiregulin and MAP3K5, which are all involved in promoting the inflammatory response. (3) Conclusions: COPD is associated with an abundance of non-polarized airway macrophages that is related to the severity of COPD. These non-polarized macrophages are predominantly responsible for the poor phagocytic capacity of lung macrophages in COPD, having reduced capacity for pathogen recognition and processing. This could be a key risk factor for COPD exacerbation and could contribute to disease progression.

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Section: Discussionmentioning

confidence: 99%

Abundance of Non-Polarized Lung Macrophages with Poor Phagocytic Function in Chronic Obstructive Pulmonary Disease (COPD)

et al. 2020

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“…Then, we performed RNA sequencing on the MSCs and compared the transcriptome of miR-146a inhibitor-MSCs with that of NC-MSCs ( Figure 2 B). In particular, we analyzed the immune response- and secretion-related genes, because MSCs control immune responses largely through the secretion of paracrine factors [ 5 , 6 , 7 ]. The data revealed that 10 genes were upregulated >three-fold and six genes downregulated >three-fold in miR-146a inhibitor-MSCs, compared to NC-MSCs ( Figure 2 B).…”

Section: Resultsmentioning

confidence: 99%

“…The data revealed that 10 genes were upregulated >three-fold and six genes downregulated >three-fold in miR-146a inhibitor-MSCs, compared to NC-MSCs ( Figure 2 B). The upregulated genes included pentraxin 3 (PTX3), tumor necrosis factor-inducible gene 6 (TSG-6), and cyclooxygenase-2 (COX-2), which are well-known to mediate the immunomodulatory actions of MSCs [ 7 , 8 , 9 , 10 , 11 , 12 ]. Meanwhile, hepatocyte growth factor (HGF) and stanniocalcin 1 (STC-1), other therapeutic factors expressed by MSCs [ 13 , 14 , 15 ], were among the downregulated genes in miR-146a inhibitor-MSCs.…”

Section: Resultsmentioning

confidence: 99%

“…In a previous study, we found that MSCs inhibited the inflammatory activation of macrophages in response to serial stimulation by lipopolysaccharide (LPS)/ adenosine triphosphate (ATP), and induced polarization of macrophages into anti-inflammatory phenotypes [7]. It has been reported that miRNAs play a critical role in the regulation of the immunomodulatory activities of MSCs [3].…”

Section: The Mirna Expression Profile Of Mscs Co-cultured With Activamentioning

confidence: 99%

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The Effect of miR-146a on the Gene Expression of Immunoregulatory Cytokines in Human Mesenchymal Stromal Cells

2020

IJMS

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Mounting evidence indicates that microRNAs (miRNAs), including miR-146a, have an impact on the immunomodulatory activities of mesenchymal stem/stromal cells (MSCs). Suppression of inflammatory macrophage activation is one of the main immunomodulatory mechanisms of MSCs. Here, we investigated whether miR-146a in MSCs might play a role in the effects of MSCs on macrophage activation. A miRNA microarray revealed that miR-146a was the most highly upregulated miRNA in MSCs upon co-culture with activated macrophages. Inhibition of miR-146a in MSCs through miR-146a inhibitor transfection had a different effect on the expression of immunoregulatory factors secreted by MSCs. Pentraxin 3, tumor necrosis factor-inducible gene 6, and cyclooxygenase-2, which are well-known mediators of the immunomodulatory functions of MSCs, were significantly upregulated in MSCs after miR-146a knockdown. By contrast, hepatocyte growth factor and stanniocalcin 1, other immunoregulatory molecules expressed by MSCs, were downregulated by miR-146a knockdown. Consequently, the inhibition of miR-146a in MSCs did not change the overall effect of MSCs on the suppression of inflammatory macrophage activation or the induction of anti-inflammatory macrophage polarization.

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“…Recently, MSCs have been demonstrated to harness macrophage derived amphiregulin (AREG) to maintain tissue homeostasis after injury. By increasing the secretion of AREG in a phagocytosis-dependent manner, MSC-primed macrophages allowed immunosuppression through the promotion of regulatory T (Treg) ( Ko et al, 2020 ).…”

Section: Cell Death As a Component Of Msc Immunomodulatory Propertiesmentioning

confidence: 99%

Mesenchymal Stromal Cell Immunology for Efficient and Safe Treatment of Osteoarthritis

Najar

Martel‐Pelletier

Pelletier

et al. 2020

Front. Cell Dev. Biol.

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Mesenchymal stem cell (MSC) therapy represents a promising approach for the treatment of osteoarthritis (OA). MSCs can be readily isolated from multiple sources and expanded ex vivo for possible clinical application. They possess a unique immunological profile and regulatory machinery that underline their therapeutic effects. They also have the capacity to sense the changes within the tissue environment to display the adequate response. Indeed, there is a close interaction between MSCs and the host cells. Accordingly, MSCs demonstrate encouraging results for a variety of diseases including OA. However, their effectiveness needs to be improved. In this review, we selected to discuss the importance of the immunological features of MSCs, including the type of transplantation and the immune and blood compatibility. It is important to consider MSC immune evasive rather than immune privileged. We also highlighted some of the actions/mechanisms that are displayed during tissue healing including the response of MSCs to injury signals, their interaction with the immune system, and the impact of their lifespan. Finally, we briefly summarized the results of clinical studies reporting on the application of MSCs for the treatment of OA. The research field of MSCs is inspiring and innovative but requires more knowledge about the immunobiological properties of these cells. A better understanding of these features will be key for developing a safe and efficient medicinal product for clinical use in OA.

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Mesenchymal Stem and Stromal Cells Harness Macrophage-Derived Amphiregulin to Maintain Tissue Homeostasis

Cited by 92 publications

References 72 publications

Abundance of Non-Polarized Lung Macrophages with Poor Phagocytic Function in Chronic Obstructive Pulmonary Disease (COPD)

Abundance of Non-Polarized Lung Macrophages with Poor Phagocytic Function in Chronic Obstructive Pulmonary Disease (COPD)

The Effect of miR-146a on the Gene Expression of Immunoregulatory Cytokines in Human Mesenchymal Stromal Cells

Mesenchymal Stromal Cell Immunology for Efficient and Safe Treatment of Osteoarthritis

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