Nuclear Magnetic Resonance Insight into the Multiple Glycosaminoglycan Binding Modes of the Link Module from Human TSG-6

Park, Younghee; Jowitt, Thomas A.; Day, Anthony J.; Prestegard, James H.

doi:10.1021/acs.biochem.5b01148

Cited by 21 publications

(22 citation statements)

References 85 publications

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“…TSG‐6 is involved in the organization and stabilization of the ECM interacting with glycosaminoglycans such as HA and heparan sulfate . In line with this, GSEA analysis showed enrichment of the “ extracellular space” gene set in WT‐MSCs compared with TSG‐6 −/− ‐MSCs (Fig.…”

Section: Resultssupporting

confidence: 66%

TNF-Stimulated Gene-6 Is a Key Regulator in Switching Stemness and Biological Properties of Mesenchymal Stem Cells

et al. 2019

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Mesenchymal stem cells (MSCs) are well established to have promising therapeutic properties. TNF‐stimulated gene‐6 (TSG‐6), a potent tissue‐protective and anti‐inflammatory factor, has been demonstrated to be responsible for a significant part of the tissue‐protecting properties mediated by MSCs. Nevertheless, current knowledge about the biological function of TSG‐6 in MSCs is limited. Here, we demonstrated that TSG‐6 is a crucial factor that influences many functional properties of MSCs. The transcriptomic sequencing analysis of wild‐type (WT) and TSG‐6−/−‐MSCs shows that the loss of TSG‐6 expression leads to the perturbation of several transcription factors, cytokines, and other key biological pathways. TSG‐6−/−‐MSCs appeared morphologically different with dissimilar cytoskeleton organization, significantly reduced size of extracellular vesicles, decreased cell proliferative rate, and loss of differentiation abilities compared with the WT cells. These cellular effects may be due to TSG‐6‐mediated changes in the extracellular matrix (ECM) environment. The supplementation of ECM with exogenous TSG‐6, in fact, rescued cell proliferation and changes in morphology. Importantly, TSG‐6‐deficient MSCs displayed an increased capacity to release interleukin‐6 conferring pro‐inflammatory and pro‐tumorigenic properties to the MSCs. Overall, our data provide strong evidence that TSG‐6 is crucial for the maintenance of stemness and other biological properties of murine MSCs.

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Section: Resultssupporting

confidence: 66%

TNF-Stimulated Gene-6 Is a Key Regulator in Switching Stemness and Biological Properties of Mesenchymal Stem Cells

et al. 2019

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“…5 B ), including a band of ∼35 kDa. It is important to note that CS is susceptible to digestion by hyaluronidase from bovine testes and that CS also binds and interacts with TSG-6 ( 64 ). TSG-6 is therefore likely to be located in the glial scar bound to the HA- and/or CS-rich matrix.…”

Section: Resultsmentioning

confidence: 99%

“…TSG-6 has been suggested to antagonize the interaction of aggrecan with HA ( 50 ). Moreover, recent work shows that TSG-6 may also cross-link CS chains ( 64 ). TSG-6 can also mediate the transfer of HCs onto chondroitin ( i.e.…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor-stimulated Gene-6 (TSG-6) Is Constitutively Expressed in Adult Central Nervous System (CNS) and Associated with Astrocyte-mediated Glial Scar Formation following Spinal Cord Injury

Coulson‐Thomas

Lauer

Soleman

et al. 2016

Journal of Biological Chemistry

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Tumor necrosis factor (TNF)-stimulated gene-6 (TSG-6) binds to hyaluronan and can reorganize/stabilize its structure, also enhancing the binding of this glycosaminoglycan to its cell surface receptor, CD44. TSG-6 is rapidly up-regulated in response to inflammatory cytokines protecting tissues from the damaging effects of inflammation. Despite TSG-6 treatment having been shown to improve outcomes in an experimental model of traumatic brain injury, TSG-6 expression has not been extensively studied in the central nervous system (CNS). We hereby analyzed the expression profile of TSG-6 in the developing CNS and following injury. We show that TSG-6 is expressed in the rat CNS by GFAP ؉ and CD44 ؉ astrocytes, solely in the mature brain and spinal cord, and is not present during the development of the CNS. TSG-6 ؊/؊ mice present a reduced number of GFAP ؉ astrocytes when compared with the littermate TSG-6 ؉/؊ mice. TSG-6 expression is drastically up-regulated after injury, and the TSG-6 protein is present within the glial scar, potentially coordinating and stabilizing the formation of this hyaluronan-rich matrix. This study shows that TSG-6 is expressed in the CNS, suggesting a role for TSG-6 in astrocyte activation and tissue repair. We hypothesize that within this context TSG-6 could participate in the formation of the glial scar and confer anti-inflammatory properties. Further studies are required to elucidate the therapeutic potential of targeting TSG-6 after CNS injury to promote its protective effects while reducing the inhibitory properties of the glial scar in axon regeneration.

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“…The ability of the TSG-6 Link module to dimerize when bound to heparin and CS ( 27 , 84 ) may contribute to its potency in sequestering chemokine-binding sites on GAGs through an avidity effect. Cross-linking of GAGs by TSG-6 may also affect the accessibility or conformation of chemokine-binding sites on GAGs.…”

Section: Discussionmentioning

confidence: 99%

The Anti-inflammatory Protein TSG-6 Regulates Chemokine Function by Inhibiting Chemokine/Glycosaminoglycan Interactions

Dyer

Salanga

Johns

et al. 2016

Journal of Biological Chemistry

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TNF-stimulated gene-6 (TSG-6) is a multifunctional protein secreted in response to pro-inflammatory stimuli by a wide range of cells, including neutrophils, monocytes, and endothelial cells. It has been shown to mediate anti-inflammatory and protective effects when administered in disease models, in part, by reducing neutrophil infiltration. Human TSG-6 inhibits neutrophil migration by binding CXCL8 through its Link module (Link_TSG6) and interfering with the presentation of CXCL8 on cell-surface glycosaminoglycans (GAGs), an interaction that is vital for the function of many chemokines. TSG-6 was also found to interact with chemokines CXCL11 and CCL5, suggesting the possibility that it may function as a broad specificity chemokine-binding protein, functionally similar to those encoded by viruses. This study was therefore undertaken to explore the ability of TSG-6 to regulate the function of other chemokines. Herein, we demonstrate that Link_TSG6 binds chemokines from both the CXC and CC families, including CXCL4, CXCL12, CCL2, CCL5, CCL7, CCL19, CCL21, and CCL27. We also show that the Link_TSG6-binding sites on chemokines overlap with chemokine GAG-binding sites, and that the affinities of Link_TSG6 for these chemokines (KD values 1–85 nm) broadly correlate with chemokine-GAG affinities. Link_TSG6 also inhibits chemokine presentation on endothelial cells not only through a direct interaction with chemokines but also by binding and therefore masking the availability of GAGs. Along with previous work, these findings suggest that TSG-6 functions as a pluripotent regulator of chemokines by modulating chemokine/GAG interactions, which may be a major mechanism by which TSG-6 produces its anti-inflammatory effects in vivo.

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Nuclear Magnetic Resonance Insight into the Multiple Glycosaminoglycan Binding Modes of the Link Module from Human TSG-6

Cited by 21 publications

References 85 publications

TNF-Stimulated Gene-6 Is a Key Regulator in Switching Stemness and Biological Properties of Mesenchymal Stem Cells

TNF-Stimulated Gene-6 Is a Key Regulator in Switching Stemness and Biological Properties of Mesenchymal Stem Cells

Tumor Necrosis Factor-stimulated Gene-6 (TSG-6) Is Constitutively Expressed in Adult Central Nervous System (CNS) and Associated with Astrocyte-mediated Glial Scar Formation following Spinal Cord Injury

The Anti-inflammatory Protein TSG-6 Regulates Chemokine Function by Inhibiting Chemokine/Glycosaminoglycan Interactions

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