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Endothelial differentiation of SHED requires MEK1/ERK signaling.

ABSTRACT: The discovery that dental pulp stem cells are capable of differentiating into endothelial cells raises the exciting possibility that these cells can be a single source of odontoblasts and vascular networks in dental tissue engineering. The purpose of this study was to begin to define signaling pathways that regulate endothelial differentiation of SHED. Stem cells from exfoliated deciduous teeth (SHED) exposed to endothelial growth medium (EGM-2MV) supplemented with vascular endothelial growth factor (VEGF) differentiated into VEGFR2-positive and CD31-positive endothelial cells in vitro. In vivo, VEGFR1-silenced SHED seeded in tooth slice/ scaffolds and transplanted into immunodeficient mice showed a reduction in human CD31-positive blood vessels as compared with controls (p = 0.02). Exposure of SHED to EGM2-MV supplemented with VEGF induced potent activation of ERK and Akt signaling, while it inhibited phosphorylation of STAT3. Notably, genetic (MEK1 silencing) or chemical (U0126) inhibition of ERK signaling restored constitutive STAT3 phosphorylation and inhibited the differentiation of SHED into endothelial cells. Collectively, analysis of these data unveiled the VEGF/MEK1/ERK signaling pathway as a key regulator of the endothelial differentiation of dental pulp stem cells.

SUBMITTER: Bento LW

PROVIDER: S-EPMC3521451 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Endothelial differentiation of SHED requires MEK1/ERK signaling.

Bento L W LW Zhang Z Z Imai A A Nör F F Dong Z Z Shi S S Araujo F B FB Nör J E JE

Journal of dental research 20121031 1

The discovery that dental pulp stem cells are capable of differentiating into endothelial cells raises the exciting possibility that these cells can be a single source of odontoblasts and vascular networks in dental tissue engineering. The purpose of this study was to begin to define signaling pathways that regulate endothelial differentiation of SHED. Stem cells from exfoliated deciduous teeth (SHED) exposed to endothelial growth medium (EGM-2MV) supplemented with vascular endothelial growth fa ...[more]

PMID: 23114032

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Project description:BackgroundConsiderable evidence shows that circular RNAs (circRNAs) play an important role in tumor development. However, their function in intrahepatic cholangiocarcinoma (ICC) metastasis and the underlying mechanisms are incompletely understood.MethodscircNFIB (hsa_circ_0086376, termed as cNFIB hereafter) was identified in human ICC tissues through circRNAs sequencing. The biological role of cNFIB was determined in vitro and in vivo by gain or loss of functional experiments. Fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down assays were conducted to analyze the interaction of cNFIB with dual specificity mitogen-activated protein kinase kinase1 (MEK1). Duolink in situ proximity ligation assay (PLA) and coimmunoprecipitation (co-IP) assay were used to investigate the effects of cNFIB on the interaction between MEK1 and mitogen-activated protein kinase 2 (ERK2). Finally, a series of in vitro and in vivo experiments were performed to explore the influences of cNFIB on the anti-tumor activity of trametinib (a MEK inhibitor).ResultscNFIB was significantly down-regulated in human ICC tissues with postoperative metastases. The loss of cNFIB was highly associated with aggressive characteristics and predicted unfavorable prognosis in ICC patients. Functional studies revealed that cNFIB inhibited the proliferation and metastasis of ICC cells in vitro and in vivo. Mechanistically, cNFIB competitively interacted with MEK1, which induced the dissociation between MEK1 and ERK2, thereby resulting in the suppression of ERK signaling and tumor metastasis. Moreover, we found that ICC cells with high levels of cNFIB held the potential to delay the trametinib resistance. Consistently, in vivo and in vitro studies demonstrated that cotreatment with trametinib and lentivirus vector encoding cNFIB showed greater inhibitory effect than isolated trametinib treatment.ConclusionsOur findings identified that cNFIB played a key role in ICC growth and metastasis by regulating MEK1/ERK signaling. Given the efficacy of cNFIB modulation on ICC suppression and trametinib sensitivity, cNFIB appears to be a potential therapeutic molecule for ICC treatment.

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Endothelial differentiation of SHED requires MEK1/ERK signaling.

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Endothelial differentiation of SHED requires MEK1/ERK signaling.

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