{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTNFAIP6, which encodes the secreted glycoprotein TSG‑6, is rapidly up‐regulated by a broad spectrum of proinflammatory mediators and growth factors in diverse cells and tissues. TSG‑6 expression is detected in inflammatory disease states such as rheumatoid arthritis and is critical during physiological remodeling processes such as ovulation, where it contributes to the expansion of the hyaluronan‐rich cumulus matrix. Its anti‐inflammatory and chondroprotective actions, demonstrated in various in vivo models, underscore its role as a negative feedback mediator that limits inflammatory responses and tissue damage."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the biochemical level, TSG‑6 acts as a multifunctional binding and catalytic protein. Its Link module binds hyaluronan and several other glycosaminoglycans, enabling TSG‑6 to mediate cross‐linking of extracellular matrix polymers and thereby alter matrix architecture. In conjunction with inter‑alpha‑inhibitor, TSG‑6 catalyzes the covalent transfer of heavy chains onto hyaluronan, stabilizing HA‑rich matrices in both inflamed and ovulatory tissues. Moreover, TSG‑6 directly interacts with key chemokines—competing with glycosaminoglycan binding sites—to inhibit neutrophil migration, while its ligand‐binding properties are modulated by factors such as pH and metal ions, allowing context‑dependent functional versatility."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its matrix‐modifying actions, TSG‑6 is a key mediator of the beneficial, immunomodulatory effects attributed to mesenchymal stem/stromal cell (MSC) therapies. MSC‑derived TSG‑6 attenuates inflammation by modulating macrophage activation—promoting a switch from a pro‑inflammatory to an antifibrotic M2 phenotype—and by suppressing the production of proinflammatory cytokines. These effects contribute to improved tissue repair and reduced fibrosis in diverse settings, including full‑thickness skin wound healing, corneal neovascularization, and lung injury. Through its ability to regulate the local inflammatory milieu and extracellular matrix composition, TSG‑6 thereby limits excessive leukocyte recruitment and matrix deposition."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional recent studies have expanded the functional repertoire of TSG‑6 to include regulation of extracellular and intracellular signaling pathways that impact tissue remodeling, bone homeostasis, and cellular regeneration. TSG‑6 modulates chemokine presentation and thereby influences leukocyte trafficking, while its interactions with growth factors and regulators of bone metabolism (including RANKL and BMPs) suggest a role in balancing osteoclast and osteoblast activities during both pathological and normal remodeling. Its involvement in mucosal healing in inflammatory bowel disease, in modulating neural and pancreatic beta‑cell signaling, and in orchestrating responses to severe tissue injury further attest to its multipotent therapeutic potential across inflammatory, fibrotic, and regenerative settings."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "36", "end_ref": "43"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Caroline M Milner, Anthony J Day "}, {"type": "b", "children": [{"type": "t", "text": "TSG-6: a multifunctional protein associated with inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.00407"}], "href": "https://doi.org/10.1242/jcs.00407"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12692188"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12692188"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Erik Fries, Aneta Kaczmarczyk "}, {"type": "b", "children": [{"type": "t", "text": "Inter-alpha-inhibitor, hyaluronan and inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Biochim Pol (2003)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14515153"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14515153"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jong-Ik Hwang, Yong-Seok Oh, Kum-Joo Shin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular cloning and characterization of a novel phospholipase C, PLC-eta."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20041677"}], "href": "https://doi.org/10.1042/BJ20041677"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15702972"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15702972"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Charles D Blundell, Andrew Almond, David J Mahoney, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Towards a structure for a TSG-6.hyaluronan complex by modeling and NMR spectroscopy: insights into other members of the link module superfamily."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M414343200"}], "href": "https://doi.org/10.1074/jbc.M414343200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15718240"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15718240"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Catalin Mindrescu, Junming Le, Hans-Georg Wisniewski, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Up-regulation of cyclooxygenase-2 expression by TSG-6 protein in macrophage cell line."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2005.03.040"}], "href": "https://doi.org/10.1016/j.bbrc.2005.03.040"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15809059"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15809059"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Marilyn S Rugg, Antony C Willis, Durba Mukhopadhyay, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of complexes formed between TSG-6 and inter-alpha-inhibitor that act as intermediates in the covalent transfer of heavy chains onto hyaluronan."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M501332200"}], "href": "https://doi.org/10.1074/jbc.M501332200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15840581"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15840581"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "David J Mahoney, Barbara Mulloy, Mark J Forster, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of the interaction between tumor necrosis factor-stimulated gene-6 and heparin: implications for the inhibition of plasmin in extracellular matrix microenvironments."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M502068200"}], "href": "https://doi.org/10.1074/jbc.M502068200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15917224"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15917224"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Svetlana A Kuznetsova, Anthony J Day, David J Mahoney, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The N-terminal module of thrombospondin-1 interacts with the link domain of TSG-6 and enhances its covalent association with the heavy chains of inter-alpha-trypsin inhibitor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M500701200"}], "href": "https://doi.org/10.1074/jbc.M500701200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16006654"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16006654"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Ana M Valdes, Mark Van Oene, Deborah J Hart, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reproducible genetic associations between candidate genes and clinical knee osteoarthritis in men and women."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arthritis Rheum (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/art.21621"}], "href": "https://doi.org/10.1002/art.21621"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16453284"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16453284"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "C M Milner, V A Higman, A J Day "}, {"type": "b", "children": [{"type": "t", "text": "TSG-6: a pluripotent inflammatory mediator?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Soc Trans (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BST0340446"}], "href": "https://doi.org/10.1042/BST0340446"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16709183"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16709183"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Rosanna Forteza, Susana M Casalino-Matsuda, Maria Elena Monzon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TSG-6 potentiates the antitissue kallikrein activity of inter-alpha-inhibitor through bikunin release."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Respir Cell Mol Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1165/rcmb.2006-0018OC"}], "href": "https://doi.org/10.1165/rcmb.2006-0018OC"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16873769"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16873769"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Svetlana A Kuznetsova, David J Mahoney, Gema Martin-Manso, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TSG-6 binds via its CUB_C domain to the cell-binding domain of fibronectin and increases fibronectin matrix assembly."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Matrix Biol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.matbio.2007.10.003"}], "href": "https://doi.org/10.1016/j.matbio.2007.10.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18042364"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18042364"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Kristian W Sanggaard, Carsten S Sonne-Schmidt, Toke P Krogager, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The transfer of heavy chains from bikunin proteins to hyaluronan requires both TSG-6 and HC2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M800874200"}], "href": "https://doi.org/10.1074/jbc.M800874200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18448433"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18448433"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "David J Mahoney, Katalin Mikecz, Tariq Ali, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TSG-6 regulates bone remodeling through inhibition of osteoblastogenesis and osteoclast activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M802138200"}], "href": "https://doi.org/10.1074/jbc.M802138200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18586671"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18586671"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Chantale Cormier, Yohan Bossé, Leandra Mfuna, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polymorphisms in the tumour necrosis factor alpha-induced protein 3 (TNFAIP3) gene are associated with chronic rhinosinusitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Otolaryngol Head Neck Surg (2009)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19344623"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19344623"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Hanne Offenberg, Nils Brünner, Francisco Mansilla, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TIMP-1 expression in human colorectal cancer is associated with TGF-B1, LOXL2, INHBA1, TNF-AIP6 and TIMP-2 transcript profiles."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Oncol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molonc.2008.06.003"}], "href": "https://doi.org/10.1016/j.molonc.2008.06.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19383344"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19383344"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Virginia Maina, Alessia Cotena, Andrea Doni, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Coregulation in human leukocytes of the long pentraxin PTX3 and TSG-6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Leukoc Biol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1189/jlb.0608345"}], "href": "https://doi.org/10.1189/jlb.0608345"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19389798"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19389798"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Igor Dzhura, Oleg G Chepurny, Grant G Kelley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Epac2-dependent mobilization of intracellular Ca²+ by glucagon-like peptide-1 receptor agonist exendin-4 is disrupted in β-cells of phospholipase C-ε knockout mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Physiol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1113/jphysiol.2010.198424"}], "href": "https://doi.org/10.1113/jphysiol.2010.198424"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21041529"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21041529"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Jung Kuk Kim, Jung Woong Choi, Seyoung Lim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phospholipase C-η1 is activated by intracellular Ca(2+) mobilization and enhances GPCRs/PLC/Ca(2+) signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2011.01.017"}], "href": "https://doi.org/10.1016/j.cellsig.2011.01.017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21262355"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21262355"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Gyorgy Nagyeri, Marianna Radacs, Sheida Ghassemi-Nejad, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TSG-6 protein, a negative regulator of inflammatory arthritis, forms a ternary complex with murine mast cell tryptases and heparin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M111.222026"}], "href": "https://doi.org/10.1074/jbc.M111.222026"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21566135"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21566135"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Svitlana Danchuk, Joni H Ylostalo, Fokhrul Hossain, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human multipotent stromal cells attenuate lipopolysaccharide-induced acute lung injury in mice via secretion of tumor necrosis factor-α-induced protein 6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cell Res Ther (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/scrt68"}], "href": "https://doi.org/10.1186/scrt68"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21569482"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21569482"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Natalia S Baranova, Erik Nilebäck, F Michael Haller, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The inflammation-associated protein TSG-6 cross-links hyaluronan via hyaluronan-induced TSG-6 oligomers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M111.247395"}], "href": "https://doi.org/10.1074/jbc.M111.247395"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21596748"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21596748"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Daria Leali, Antonio Inforzato, Roberto Ronca, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Long pentraxin 3/tumor necrosis factor-stimulated gene-6 interaction: a biological rheostat for fibroblast growth factor 2-mediated angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arterioscler Thromb Vasc Biol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/ATVBAHA.111.243998"}], "href": "https://doi.org/10.1161/ATVBAHA.111.243998"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22267482"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22267482"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Mark E Lauer, Georgiana Cheng, Shadi Swaidani, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tumor necrosis factor-stimulated gene-6 (TSG-6) amplifies hyaluronan synthesis by airway smooth muscle cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.389882"}], "href": "https://doi.org/10.1074/jbc.M112.389882"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23129777"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23129777"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Mark E Lauer, Tibor T Glant, Katalin Mikecz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Irreversible heavy chain transfer to hyaluronan oligosaccharides by tumor necrosis factor-stimulated gene-6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.403998"}], "href": "https://doi.org/10.1074/jbc.M112.403998"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23166324"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23166324"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Lianghui Zhang, Sundeep Malik, Jinjiang Pang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phospholipase Cε hydrolyzes perinuclear phosphatidylinositol 4-phosphate to regulate cardiac hypertrophy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2013.02.047"}], "href": "https://doi.org/10.1016/j.cell.2013.02.047"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23540699"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23540699"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Yu Qi, Dongsheng Jiang, Anca Sindrilaru, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TSG-6 released from intradermally injected mesenchymal stem cells accelerates wound healing and reduces tissue fibrosis in murine full-thickness skin wounds."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Invest Dermatol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/jid.2013.328"}], "href": "https://doi.org/10.1038/jid.2013.328"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23921952"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23921952"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Natalia S Baranova, Simon J Foulcer, David C Briggs, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inter-α-inhibitor impairs TSG-6-induced hyaluronan cross-linking."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.477422"}], "href": "https://doi.org/10.1074/jbc.M113.477422"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24005673"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24005673"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Douglas P Dyer, Jennifer M Thomson, Aurelie Hermant, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TSG-6 inhibits neutrophil migration via direct interaction with the chemokine CXCL8."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1300194"}], "href": "https://doi.org/10.4049/jimmunol.1300194"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24501198"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24501198"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Hui Wang, Zhao Chen, Xiao-Jing Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Anti-inflammatory cytokine TSG-6 inhibits hypertrophic scar formation in a rabbit ear model."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Pharmacol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejphar.2015.01.040"}], "href": "https://doi.org/10.1016/j.ejphar.2015.01.040"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25661977"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25661977"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "David C Briggs, Holly L Birchenough, Tariq Ali, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Metal Ion-dependent Heavy Chain Transfer Activity of TSG-6 Mediates Assembly of the Cumulus-Oocyte Matrix."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M115.669838"}], "href": "https://doi.org/10.1074/jbc.M115.669838"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26468290"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26468290"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Darwin J Prockop "}, {"type": "b", "children": [{"type": "t", "text": "Inflammation, fibrosis, and modulation of the process by mesenchymal stem/stromal cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Matrix Biol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.matbio.2016.01.010"}], "href": "https://doi.org/10.1016/j.matbio.2016.01.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26807758"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26807758"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Douglas P Dyer, Catherina L Salanga, Scott C Johns, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Anti-inflammatory Protein TSG-6 Regulates Chemokine Function by Inhibiting Chemokine/Glycosaminoglycan Interactions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M116.720953"}], "href": "https://doi.org/10.1074/jbc.M116.720953"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27044744"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27044744"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "John Martin, Adam Midgley, Soma Meran, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tumor Necrosis Factor-stimulated Gene 6 (TSG-6)-mediated Interactions with the Inter-α-inhibitor Heavy Chain 5 Facilitate Tumor Growth Factor β1 (TGFβ1)-dependent Fibroblast to Myofibroblast Differentiation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M115.670521"}], "href": "https://doi.org/10.1074/jbc.M115.670521"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27143355"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27143355"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Lingying Liu, Huifeng Song, Hongjie Duan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TSG-6 secreted by human umbilical cord-MSCs attenuates severe burn-induced excessive inflammation via inhibiting activations of P38 and JNK signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep30121"}], "href": "https://doi.org/10.1038/srep30121"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27444207"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27444207"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Woo-Jin Song, Qiang Li, Min-Ok Ryu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TSG-6 Secreted by Human Adipose Tissue-derived Mesenchymal Stem Cells Ameliorates DSS-induced colitis by Inducing M2 Macrophage Polarization in Mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-017-04766-7"}], "href": "https://doi.org/10.1038/s41598-017-04766-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28701721"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28701721"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Guan Wang, Kai Cao, Keli Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Kynurenic acid, an IDO metabolite, controls TSG-6-mediated immunosuppression of human mesenchymal stem cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Differ (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41418-017-0006-2"}], "href": "https://doi.org/10.1038/s41418-017-0006-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29238069"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29238069"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Hyun Beom Song, Se Yeon Park, Jung Hwa Ko, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mesenchymal Stromal Cells Inhibit Inflammatory Lymphangiogenesis in the Cornea by Suppressing Macrophage in a TSG-6-Dependent Manner."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Ther (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ymthe.2017.09.026"}], "href": "https://doi.org/10.1016/j.ymthe.2017.09.026"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29301108"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29301108"}]}, {"type": "r", "ref": 39, "children": [{"type": "t", "text": "Anthony J Day, Caroline M Milner "}, {"type": "b", "children": [{"type": "t", "text": "TSG-6: A multifunctional protein with anti-inflammatory and tissue-protective properties."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Matrix Biol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.matbio.2018.01.011"}], "href": "https://doi.org/10.1016/j.matbio.2018.01.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29362135"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29362135"}]}, {"type": "r", "ref": 40, "children": [{"type": "t", "text": "Qiang Li, Woo-Jin Song, Min-Ok Ryu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TSG-6 secreted by human adipose tissue-derived mesenchymal stem cells ameliorates severe acute pancreatitis via ER stress downregulation in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cell Res Ther (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13287-018-1009-8"}], "href": "https://doi.org/10.1186/s13287-018-1009-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30257717"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30257717"}]}, {"type": "r", "ref": 41, "children": [{"type": "t", "text": "May J Reed, Mamatha Damodarasamy, Jasmine L Pathan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased Hyaluronan and TSG-6 in Association with Neuropathologic Changes of Alzheimer's Disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Alzheimers Dis (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3233/JAD-180797"}], "href": "https://doi.org/10.3233/JAD-180797"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30507579"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30507579"}]}, {"type": "r", "ref": 42, "children": [{"type": "t", "text": "Aurelie Dos Santos, Alis Balayan, Martha L Funderburgh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differentiation Capacity of Human Mesenchymal Stem Cells into Keratocyte Lineage."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Invest Ophthalmol Vis Sci (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1167/iovs.19-27008"}], "href": "https://doi.org/10.1167/iovs.19-27008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31310658"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31310658"}]}, {"type": "r", "ref": 43, "children": [{"type": "t", "text": "Hongsheng Yang, Rui Feng, Qingling Fu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human induced pluripotent stem cell-derived mesenchymal stem cells promote healing via TNF-α-stimulated gene-6 in inflammatory bowel disease models."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-019-1957-7"}], "href": "https://doi.org/10.1038/s41419-019-1957-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31558705"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31558705"}]}]}]}