TNF-α-induced endothelial differentiation of human mesenchymal stem cells
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ABSTRACT:
PROVIDER: PRJNA887370 | ENA |
REPOSITORIES: ENA
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Project description:Mesenchymal stem cells (MSCs) can differentiate into endothelial cells; however, the mechanisms underlying this process in the tumor microenvironment (TME) remain elusive. This study shows that tumor necrosis factor alpha (TNF-α), a key cytokine present in the TME, promotes the endothelial differentiation of MSCs by inducing vascular endothelial growth factor receptor 2 (VEGFR2) gene expression. EGR1 is a member of the zinc-finger transcription factor family induced by TNF-α. Our findings indicate that EGR1 directly binds to the VEGFR2 promoter and transactivates VEGFR2 expression. We also demonstrate that EGR1 forms a complex with c-JUN activated by c-JUN N-terminal kinase (JNK) to promote VEGFR2 transcription and endothelial differentiation in MSCs in response to TNF-α stimulation. The shRNA-mediated silencing of EGR1 or c-JUN abrogates TNF-α-induced VEGFR2 transcription and the endothelial differentiation of MSCs. Collectively, these findings demonstrate that the JNK-EGR1 signaling axis plays a crucial role in the TNF-α-induced endothelial differentiation of MSCs in the TME, which could be a potential therapeutic target for solid tumors vasculatures.
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Project description:Endothelial-mesenchymal-transition (EndMT) is an important source of cancer-associated fibroblasts (CAFs), which are known to facilitate tumor progression. We have previously shown that EndMT is present in pancreatic tumors and that deficiency of the Tie1 receptor induces EndMT in human endothelial cells. Pancreatic tumors are characterized by the presence of tumor necrosis factor-α (TNF-α). We now show that TNF-α strongly induces human endothelial cells to undergo EndMT. In order to know the secretory feature of cells which undergo EndMT by TNF-α, we conducted a comparative analysis of HMVEC secretome treated or not for 24h and 48h with TNF-α. Secretome study shows that cells treated with TNF-α have an important fibroblast-like secretory capacity, and a proinflamatory signature. Moreover, Ingenuity Pathway Analysis (IPA) shows that pathways implicated in migration, inflammation and fibrosis are predicted to be activated and that necrosis and apoptosis pathways are inhibited. Accordingly cell survival, viability and cycle progression are activated. We show that TNF-α- treated cells secrete proteins related to 16 protumoral pathways, confirming their fibroblastic characteristic. Finally, among the predicted upstream regulators activated, IPA analysis shows that, TNFSF12 and its receptor are present at hight levels in PDAC patients. Altogether these results show the fibroblastic characteristic of treated cells and demonstrate that TNF-α induces CAFs.
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Project description:TNF-alpha has a number of pro-atherogenic effects in macrovascular endothelial cells, including induction of leukocyte adhesion molecules and chemokines. We investigated the role of acyl-CoA synthetase 3 (ACSL3) in the response of cultured human macrovascular endothelial cells to TNF-alpha. TNF-alpha induced ACSL3 both in human umbilical vein endothelial cells (HUVECs) and in human coronary artery endothelial cells (HCAECs). RNA sequencing demonstrated that knockdown of ACSL3 had no marked effects on the TNF-alpha transcriptome in HCAECs. Instead, ACSL3 was required for TNF-alpha-induced lipid droplet formation from fatty acids.
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Project description:Obesity is a clinical condition characterised by a chronic, low-grade inflammatory state. Adipose-derived mesenchymal stem cells (ADSCs) have a multidirectional differentiation potential to adipocytes. However, the relationship between adipogenesis and inflammation is not yet fully understood.TAZ (WW domain containing transcription regulator 1) can act as a molecular rheostat to fine-tune the osteoblast and adipocyte differentiation balance. In this study, we investigated the role of TAZ in the adipogenesis of Arbas cashmere goat ADSCs (gADSCs). We observed elevated TAZ expression levels during the adipogenesis of gADSCs. Overexpression and knockdown of TAZ were performed in stably transfected gADSCs cell lines, and RNA-seq analysis revealed that TAZ was associated with adipogenesis. TAZ overexpression promoted adipose differentiation of gADSCs, while TAZ knockdown had the opposite effect. In addition, TAZ overexpression and knockdown altered the expression of YAP1 (Yes1 associated transcriptional regulator) and TAZ in the nucleus. TAZ regulated the mRNA expression level and secretion level of tumor necrosis factor (TNF)-α, promoting adipose differentiation of gADSCs. Notably, TNF-α counteracted the inhibitory effect of sh-TAZ on the adipose differentiation of gADSCs. Collectively, these findings suggest that TAZ regulates adipogenesis in gADSCs by modulating TNF-α, which is of particular significance in several metabolic disorders where the amount or function of adipose tissue is altered.
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