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

Abstract

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.

Tumor necrosis factor-inducible gene 6 interacts with CD44, which is involved in fate-change of hepatic stellate cells

“…Tumor necrosis factor-inducible gene 6 protein (TSG-6), one of cytokines released from mesenchymal stem cells (MSCs), is also involved in maintaining the stem cell properties of MSCs (1,2). TSG-6 suppression in bone marrow-derived MSCs results in them losing their morphology, proliferative ability and differentiation capacity (2).…”

“…Tumor necrosis factor-inducible gene 6 protein (TSG-6), one of cytokines released from mesenchymal stem cells (MSCs), is also involved in maintaining the stem cell properties of MSCs (1,2). TSG-6 suppression in bone marrow-derived MSCs results in them losing their morphology, proliferative ability and differentiation capacity (2). In addition, we previously reported that TSG-6 induces hepatic stellate cells (HSCs) to gain stemness by activating yes-associated protein 1 (YAP-1), which is a well-known factor associated with stemness, resulting in reprogramming of HSCs into stem cell-like cells (3).…”

Bone marrow-derived humoral factors suppress oxidative phosphorylation, upregulate TSG-6, and improve therapeutic effects on liver injury of mesenchymal stem cells

“…Furthermore, it is reported that TSG-6-deficient MSCs exhibit morphological changes similar to senescent or degraded MSCs and show a reduction in their proliferation and differentiation potentials, indicating that the TSG-6 produced by MSCs possibly helps to maintain the stemness of the MSCs themselves. (38) The bone marrow (BM) and liver are closely interlinked in adult humans, (39,40) and the niche for stem/progenitor cells in the BM and liver share some similarities. MSCs are well known for their important role in establishing a niche for hematopoietic stem cells (HSCs) in BM, (41) and their possible involvement in niche formation of hepatic progenitor cells in the liver has also been reported.…”

Mesenchymal perivascular cells in immunity and disease

“…TNF-stimulated gene-6 (TSG-6), an inflammation-associated secreted protein that has diverse tissue protective and properties, has been shown to play a role in the anti-inflammatory capacities of MSCs. TSG-6-deficient MSCs have decreased proliferation capacity and display altered expression of several transcription factors and cytokines controlling inflammation, including IL-6 [ 37 , 38 ].…”