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IGFBP2 enhances adipogenic differentiation potentials of mesenchymal stem cells from Wharton's jelly of the umbilical cord via JNK and Akt signaling pathways.

ABSTRACT: Mesenchymal stem cell (MSC)-mediated tissue engineering represents a promising strategy to address adipose tissue defects. MSCs derived from Wharton's jelly of the umbilical cord (WJCMSCs) may serve as an ideal source for adipose tissue engineering due to their abundance, safety profile, and accessibility. How to activate the directed differentiation potentials of WJCMSCs is the core point for their clinical applications. A thorough investigation of mechanisms involved in WJCMSC adipogenic differentiation is necessary to support their application in adipose tissue engineering and address shortcomings. Previous study showed, compared with periodontal ligament stem cells (PDLSCs), WJCMSCs had a weakened adipogenic differentiation potentials and lower expression of insulin-like growth factor binding protein 2 (IGFBP2). IGFBP2 may be involved in the adipogenesis of MSCs. Generally, IGFBP2 is involved in regulating biological activity of insulin-like growth factors, however, its functions in human MSCs are unclear. Here, we found IGFBP2 expression was upregulated upon adipogenic induction, and that IGFBP2 enhanced adipogenic differentiation of WJCMSCs and BMSCs. Moreover, IGFBP2 increased phosphorylation of c-Jun N-terminal kinase (p-JNK) and p-Akt, and activated JNK or Akt signaling significantly promoted adipogenic differentiation of MSCs. Furthermore, inhibitor-mediated blockage of either JNK or Akt signaling dramatically reduced IGFBP2-mediated adipogenic differentiation. And the JNK inhibitor, SP600125 markedly blocked IGFBP2-mediated Akt activation. Moreover, IGFBP2 was negatively regulated by BCOR, which inhibited adipogenic differentiation of WJCMSCs. Overall, our results reveal a new function of IGFBP2, providing a novel insight into the mechanism of adipogenic differentiation and identifying a potential target mediator for improving adipose tissue engineering based on WJCMSCs.

SUBMITTER: Wang Y

PROVIDER: S-EPMC5578624 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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IGFBP2 enhances adipogenic differentiation potentials of mesenchymal stem cells from Wharton's jelly of the umbilical cord via JNK and Akt signaling pathways.

Wang Yuejun Y Liu Yunsong Y Fan Zhipeng Z Liu Dayong D Wang Fu F Zhou Yongsheng Y

PloS one 20170831 8

Mesenchymal stem cell (MSC)-mediated tissue engineering represents a promising strategy to address adipose tissue defects. MSCs derived from Wharton's jelly of the umbilical cord (WJCMSCs) may serve as an ideal source for adipose tissue engineering due to their abundance, safety profile, and accessibility. How to activate the directed differentiation potentials of WJCMSCs is the core point for their clinical applications. A thorough investigation of mechanisms involved in WJCMSC adipogenic diffe ...[more]

PMID: 28859160

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Project description:ObjectivesMesenchymal stem cell (MSC)-mediated tissue regeneration represents a promising strategy for repair of tissue defects, but its molecular mechanisms remain unclear, restricting the use of MSCs. Our previous study indicated that insulin-like growth factor-binding protein 5 (IGFBP5) exerted a valuable effect on osteogenic differentiation of MSCs, but its molecular mechanisms underlying directed differentiation remained unclear. In this study, we have investigated the molecular role of IGFBP5 in regulating this osteogenic differentiation potential.Materials and methodsPeriodontal ligament stem cells (PDLSCs) were isolated from periodontal ligament tissue. Wharton's jelly of umbilical cord stem cells (WJCMSCs) was obtained commercially. Lentiviral IGFBP5 shRNA was used to silence IGFBP5. Retroviruses expressing wild-type IGFBP5 were used to overexpress IGFBP5 in the WJCMSCs. Recombinant human IGFBP5 protein (rhIGFBP5) was used to treat PDLSCs for 24 h. Western blot analysis was used to detect the MAPK signalling pathway, and alkaline phosphatase (ALP) activity, Alizarin Red staining and quantitative calcium analysis were used to study osteogenic differentiation potentials.ResultsOverexpression of IGFBP5 or rhIGFBP5 increased expression levels of phosphorylated c-Jun N-terminal kinase (p-JNK), phosphorylated mitogen-activated protein kinase 1 and 2 (p-MEK1/2) and phosphorylated extracellular regulated protein kinases (p-Erk1/2) in both WJCMSCs and PDLSCs. Consistently, silenced IGFBP5 was found to effectively inhibit expression of p-JNK, p-Erk1/2 and p-MEK1/2 in PDLSCs and WJCMSCs. Furthermore, inhibition of JNK by its inhibitor, SP600125, or MEK/Erk signalling by its inhibitor, PD98059, dramatically blocked IGFBP5-enhanced ALP activity and in vitro mineralization in both PDLSCs and WJCMSCs.ConclusionsOur results demonstrated that IGFBP5 promoted osteogenic differentiation potentials of PDLSCs and WJCMSCs via the JNK and MEK/Erk signalling pathways.

Project description:Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) are a novel and promising strategy for tissue engineering because of their ability to differentiate into many cell types. We characterized the differentiation of WJ-MSCs into endometrial epithelial cell (EEC)-like and endometrial stromal cell (ESC)-like cells and assessed the effect of 17?-estradiol and 8-Br-cAMP on the differentiation system.WJ-MSCs were treated in two ways to differentiate into EEC-like and ESC-like cells respectively: cocultured with ESCs in control/differentiation medium (17?-estradiol, growth factors); and cultured in control/differentiation medium (8-Br-cAMP alone or 8-Br-cAMP plus 17?-estrogen and growth factors). Three signaling pathway inhibitors (SB203580, PD98059, H89) were used to investigate the mechanism of WJ-MSC differentiation into ESC-like cells. Immunofluorescence, western blot and flow cytometry analyses were used to analyze expression of epithelial markers and stromal cell markers. Enzyme-linked immunosorbent assays were used to test the production of secretory proteins associated with the differentiation of ESC-like cells.17?-estradiol at 1 ?M downregulated vimentin and CD13 and upregulated cytokeratin and CD9 proteins, promoting the differentiation of WJ-MSCs into EEC-like cells in the coculture system. 8-Br-cAMP at 0.5 mM upregulated vimentin and CD13 and downregulated CK and CD9, promoting the differentiation of WJ-MSCs into ESC-like cells. Prolactin (PRL) and insulin-like growth factor-binding protein 1 (IGFBP1) were upregulated and the protein kinase A (PKA) signaling pathway was activated, whereas extracellular signal-regulated (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) were not affected.17?-estradiol at 1 ?M is a good inducer for facilitating the differentiation of WJ-MSCs into EEC-like cells. 8-Br-cAMP plus estrogen and growth factors can induce the differentiation of WJ-MSCs into ESC-like cells. During the differentiation of WJ-MSCs into ESC-like cells, PRL and IGFBP1 were upregulated by the treatment and the PKA signaling pathway was activated, whereas ERK1/2 and p38 MAPK were not affected. These findings suggest a promising approach to the treatment of endometrial damage and other endometrial diseases and suggest new applications for WJ-MSCs in clinical practice.

Project description:BACKGROUND:Keloid formation occurs in Caucasian, African, and Asian populations and is a severe psychosocial burden on patients. There is no permanent treatment for this problem as its pathogenesis is not properly understood. Furthermore, differences in keloid behavior between ethnic groups are not known. It has been hypothesized that keloids behave like benign tumors because of their uncontrolled growth. The present study evaluated the tumoricidal properties of human Wharton's jelly stem cell-conditioned medium (hWJSC-CM) on fresh Asian keloid cells (AKCs). METHODS:Human Wharton's jelly stem cells (hWJSCs) and AKCs were isolated based on our previous methods. hWJSCs and human skin fibroblasts (HSF) (controls) were used to collect hWJSC-CM and HSF-conditioned medium (HSF-CM). AKCs were treated with hWJSC-CM and HSF-CM in vitro and in vivo in a human keloid xenograft SCID mouse model. The inhibitory effect of hWJSC-CM on AKCs was tested in vitro using various assays and in vivo for attenuation/abrogation of AKC tumors created in a xenograft mouse model. RESULTS:qRT-PCR analysis showed that the genes FN1, MMP1, and VCAN were significantly upregulated in AKCs and ANXA1, ASPN, IGFBP7, LGALS1, and PTN downregulated. AKCs exposed to hWJSC-CM in vitro showed significant decreases in cell viability and proliferation, increases in Annexin V-FITC+ cell numbers, interruptions of the cell cycle at Sub-G1 and G2/M phases, altered CD marker expression, downregulated anti-apoptotic-related genes, and upregulated pro-apoptotic and autophagy-related genes compared to controls. When AKCs were administered together with hWJSC-CM into immunodeficient mice there were no keloid tumors formed in 7 mice (n =?10) compared to the untreated control mice. When hWJSC-CM was injected directly into keloid tumors created in mice there were significant reductions in keloid tumor volumes and weights in 30?days. CONCLUSIONS:hWJSC-CM inhibited the growth of AKCs in vitro and in xenograft mice, and it may be a potential novel treatment for keloids in the human. The specific molecule(s) in hWJSC-CM that induce the anti-keloid effect need to be identified, characterized, and tested separately in larger preclinical and clinical studies.

Dataset Information

IGFBP2 enhances adipogenic differentiation potentials of mesenchymal stem cells from Wharton's jelly of the umbilical cord via JNK and Akt signaling pathways.

Publications

IGFBP2 enhances adipogenic differentiation potentials of mesenchymal stem cells from Wharton's jelly of the umbilical cord via JNK and Akt signaling pathways.

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