CREB/Wnt10b mediates the effect of COX‐2 on promoting BMP9‐induced osteogenic differentiation via reducing adipogenic differentiation in mesenchymal stem cells

Liao, Yun-Peng; Du, Weimin; Ying, Hanjie; Li, Fu-Shu; Ma, Yan; Wang, Han; Zhu, Jiahui; Li, Qin; Su, Yuxi

doi:10.1002/jcb.28234

Cited by 15 publications

(14 citation statements)

References 49 publications

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“…In macrophages, the expression of cAMP-responsive element-binding protein (CREB) [ 33 ] inhibits AP1, which are involved in the expression of iNOS, IL6, TNF, and IL1 [ 34 ]. Additionally, CREB expression has been described in MSCs, regulating COX2 function [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Time-dependent LPS exposure commands MSC immunoplasticity through TLR4 activation leading to opposite therapeutic outcome in EAE

et al. 2020

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Background Mesenchymal stem cells (MSCs) have been recognized for their regenerative and anti-inflammatory capacity which makes them very attractive to cell therapy, especially those ones to treat inflammatory and autoimmune disease. Two different immune-phenotypes have been described for MSCs depending on which Toll-like receptor (TLR) is activated. MSC1 is endowed with a pro-inflammatory phenotype following TLR4 activation with LPS. On the other hand, anti-inflammatory MSC2 is induced by the activation of TLR3 with Poly(I:C). High immunoplasticity of MSCs is a matter of concern in cell-based therapies. In this study, we investigated whether a single stimulus can induce both types of MSCs through a differential activation of TLR4 with LPS. Methods MSCs were activated with LPS following a short exposure of 1-h (MSCs-LPS1h) or long-time exposure for 48 h (MSCs-LPS48h), and then, we evaluated the biological response in vitro, the immunosuppressive capacity of MSCs in vitro, and the therapeutic potential of MSCs in an experimental autoimmune encephalomyelitis (EAE) mouse model. Results Our results showed that 1-h LPS exposure induced a MSC1 phenotype. Indeed, MSCs-LPS1h expressed low levels of NO/iNOS and decreased immunosuppressive capacity in vitro without therapeutic effect in the EAE model. In contrast, MSCs-LPS48h achieved a MSC2-like phenotype with significant increase in the immunosuppressive capacity on T cell proliferation in vitro, together with an improved in the therapeutic effect and higher Treg, compared to unstimulated MSCs. Furthermore, we determine through the MSCs-TLR4KO that the expression of TLR4 receptor is essential for MSCs’ suppressive activity since TLR4 deletion was associated with a diminished suppressive effect in vitro and a loss of therapeutic effect in vivo. Conclusions We demonstrate that MSCs display a high immunoplasticity commanded by a single stimulus, where LPS exposure time regulated the MSC suppressive effect leading into either an enhanced or an impairment therapeutic activity. Our results underscore the importance of phenotype conversion probably related to the TLR4 expression and activation, in the design of future clinical protocols to treat patients with inflammatory and autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Time-dependent LPS exposure commands MSC immunoplasticity through TLR4 activation leading to opposite therapeutic outcome in EAE

et al. 2020

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“…Together, we revealed the role of linc02349 as a ceRNA for miR‐25‐3p/33b‐5p. Wnt10b shifts cell fate towards the osteoblast lineage by induction of the osteoblastogenic transcription factors SMAD5, Dlx5 and OSX 25,45,46 . SMAD5 is the gene involving BMP signal and promotes osteogenic differentiation of MSC 26 .…”

Section: Discussionmentioning

confidence: 99%

Linc02349 promotes osteogenesis of human umbilical cord‐derived stem cells by acting as a competing endogenous RNA for miR‐25‐3p and miR‐33b‐5p

et al. 2020

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Objectives: Increasing evidences suggest that inducing mesenchymal stem cells to differentiate into osteoblasts has been as an especially important component in the prevention and therapy for degenerative bone disease. Here, we identify a novel lncRNA, linc02349, which increases significantly during osteogenic differentiation. Materials and methods:Human umbilical cord-derived stem cells (hUC-MSCs) and dental pulp mesenchymal stem cells were used. Overexpression and knockdown of linc02349 in cell lines were generated using lentiviral-mediated gene delivery method.Bioinformatics prediction, Ago2-RIP assay and dual-luciferase reporter system were employed to examine miRNA which interacts with linc02349. The RNA FISH assay was performed to identify the subcelluar location of linc02349. Alizarin Red S staining, ALP staining and qPCR were applied to identify the osteogenic differentiation. The potential linc02349-regulated genes, miR-25-3p and miR-33b-5p, were explored by ChIP, RIP and Western blotting assays. Micro-CT was used to measure the osteogenic content in bone formation assay in vivo. Results: Linc02349 overexpression improves osteogenic differentiation by in vitroand in vivo analysis. Mechanistically, linc02349 acts as a molecular sponge for miR-25-3p and miR-33b-5p to control expression abundance of SMAD5 and Wnt10b,

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“…For example, bone morphogenetic protein-2 promotes osteosarcoma growth, BMP5 regulates neural crest cell survival, BMP7 possesses anti-cancer activity through non-canonical BMPs/Smads signaling pathway and BMP9 induces osteogenic differentiation. 17 , 18 , 19 , 20 But there is an uneven distribution of concerns about the various aspects of the role of BMP9 in cancers. 21 , 22 Moreover, it was reported that the anti-cancer activity of Res(resveratrol), which is also isolated from the Chinese herbal medicine, may directly up-regulate BMP9 expression to activate p38 MAPK in colon cancer, 23 so whether BMP9 participates in the anti-cancer effect of Tet has aroused our concern.…”

Section: Introductionmentioning

confidence: 99%

Tetrandrine inhibits proliferation of colon cancer cells by BMP9/ PTEN/ PI3K/AKT signaling

Liu

Ding

et al. 2021

Genes & Diseases

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Despite advances in screening and treatment, colon cancer remains one of the leading causes of cancer-related death. Finding novel and useful drug treatment targets is also an urgent need for clinical applications. Tetrandrine (Tet) is extracted from the Chinese medicinal herbal medicine, which is a well-known calcium blocker with a variety of pharmacological activities, including anti-cancer. In this study, we recruited cell viability assay, flow cytometry analysis, cloning formation to confirm that Tet can inhibit the proliferation of SW620 cells, and induce apoptosis. Mechanically, we confirmed that Tet up-regulates the mRNA and protein level of BMP9 in SW620 cells. Over-expression BMP9 enhances the anti-cancer effects of Tet in SW620 cells, but these effects can be partly reversed by silencing BMP9. Also, Tet reduces phosphorylation of Aktl/2/3 in SW620 cells, which could be elevated by overexpressed BMP9 and impaired by silencing BMP9. Furthermore, we demonstrated that Tet reduces phosphorylated PTEN, which can be promoted by overexpressed BMP9, analogously also be attenuated through silencing BMP9. Finally, we introduced a xenograft tumor model to investigate the anti-proliferative effect of Tet, further to explore the effects of BMP9 and PTEN in SW620 cells. Our findings suggested that the anti-cancer activity of Tet in SW620 cells may be mediated partly by up-regulating BMP9, followed by inactivation PI3K/Akt through up-regulating PTEN at least.

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CREB/Wnt10b mediates the effect of COX‐2 on promoting BMP9‐induced osteogenic differentiation via reducing adipogenic differentiation in mesenchymal stem cells

Cited by 15 publications

References 49 publications

Time-dependent LPS exposure commands MSC immunoplasticity through TLR4 activation leading to opposite therapeutic outcome in EAE

Time-dependent LPS exposure commands MSC immunoplasticity through TLR4 activation leading to opposite therapeutic outcome in EAE

Linc02349 promotes osteogenesis of human umbilical cord‐derived stem cells by acting as a competing endogenous RNA for miR‐25‐3p and miR‐33b‐5p

Tetrandrine inhibits proliferation of colon cancer cells by BMP9/ PTEN/ PI3K/AKT signaling

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