CXCL12 increases human neural progenitor cell proliferation through Akt‐1/FOXO3a signaling pathway

Wu, Yumei; Peng, Hui; Cui, Min; Whitney, Nicholas P.; Huang, Yunlong; Zheng, Jialin

doi:10.1111/j.1471-4159.2009.06043.x

Cited by 106 publications

(97 citation statements)

References 75 publications

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“…The effect of inflammatory factors on NSPCs has been studied and a variety of responses have been discovered (Ziv and Schwartz, 2008;Carpentier and Palmer, 2009;Russo et al, 2011). TNF-a, IL-1b, and SDF1 (CXCL12) are capable of increasing NSPC proliferation Wu et al, 2009). In this study, we showed that MIF can increase the proliferation and/or survival of NSPCs, as was seen with SDF1.…”

Section: Discussionsupporting

confidence: 53%

Macrophage migration inhibitory factor (MIF) promotes cell survival and proliferation of neural stem/progenitor cells

Ohta

Misawa

Fukaya

et al. 2012

Journal of Cell Science

117

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SummaryIn a previous study, we showed that murine dendritic cells (DCs) can increase the number of neural stem/progenitor cells (NSPCs) in vitro and in vivo. In the present study, we identified macrophage migration inhibitory factor (MIF) as a novel factor that can support the proliferation and/or survival of NSPCs in vitro. MIF is secreted by DCs and NSPCs, and its function in the normal brain remains largely unknown. It was previously shown that in macrophages, MIF binds to a CD74-CD44 complex. In the present study, we observed the expression of MIF receptors in mouse ganglionic-eminence-derived neurospheres using flow cytometry in vitro. We also found CD74 expression in the ganglionic eminence of E14 mouse brains, suggesting that MIF plays a physiological role in vivo. MIF increased the number of primary and secondary neurospheres. By contrast, retrovirally expressed MIF shRNA and MIF inhibitor (ISO-1) suppressed primary and secondary neurosphere formation, as well as cell proliferation. In the neurospheres, MIF knockdown by shRNA increased caspase 3/7 activity, and MIF increased the phosphorylation of Akt, Erk, AMPK and Stat3 (Ser727), as well as expression of Hes3 and Egfr, the products of which are known to support cell survival, proliferation and/or maintenance of NSPCs. MIF also acted as a chemoattractant for NSPCs. These results show that MIF can induce NSPC proliferation and maintenance by multiple signaling pathways acting synergistically, and it may be a potential therapeutic factor, capable of activating NSPC, for the treatment of degenerative brain disorders.

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Section: Discussionsupporting

confidence: 53%

Macrophage migration inhibitory factor (MIF) promotes cell survival and proliferation of neural stem/progenitor cells

Ohta

Misawa

Fukaya

et al. 2012

Journal of Cell Science

117

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“…Sporadic studies indicated that CXCL12 mediated the proliferation of cancer cells, which may be related to activation of Akt, Erk, Akt-1/FOXO-3␣, Stat-3, and etc. (7,20,21,30,31). Although additional study is warranted to elucidate the correlation between rapamycin anti-proliferation activity and cxcl12 expression, this finding further supports that mTOR inhibitor may be useful for gastric cancer therapy.…”

Section: Discussionmentioning

confidence: 55%

Inhibition of Chemokine (CXC Motif) Ligand 12/Chemokine (CXC Motif) Receptor 4 Axis (CXCL12/CXCR4)-mediated Cell Migration by Targeting Mammalian Target of Rapamycin (mTOR) Pathway in Human Gastric Carcinoma Cells

Chen

Wang

et al. 2012

Journal of Biological Chemistry

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CXCL12/CXCR4 plays an important role in metastasis of gastric carcinoma. Rapamycin has been reported to inhibit migration of gastric cancer cells. However, the role of mTOR pathway in CXCL12/CXCR4-mediated cell migration and the potential of drugs targeting PI3K/mTOR pathway remains unelucidated. We found that CXCL12 activated PI3K/Akt/mTOR pathway in MKN-45 cells. Stimulating CHO-K1 cells expressing pEGFP-C1-Grp1-PH fusion protein with CXCL12 resulted in generation of phosphatidylinositol (3,4,5)-triphosphate, which provided direct evidence of activating PI3K by CXCL12. Down-regulation of p110β by siRNA but not p110α blocked phosphorylation of Akt and S6K1 induced by CXCL12. Consistently, p110β-specific inhibitor blocked the CXCL12-activated PI3K/Akt/mTOR pathway. Moreover, CXCR4 immunoprecipitated by anti-p110β antibody increased after CXCL12 stimulation and Gi protein inhibitor pertussis toxin abrogated CXCL12-induced activation of PI3K. Further studies demonstrated that inhibitors targeting the PI3K/mTOR pathway significantly blocked the chemotactic responses of MKN-45 cells triggered by CXCL12, which might be attributed primarily to inhibition of mTORC1 and related to prevention of F-actin reorganization as well as down-regulation of active RhoA, Rac1, and Cdc42. Furthermore, rapamycin inhibited the secretion of CXCL12 and the expression of CXCR4, which might form a positive feedback loop to further abolish upstream signaling leading to cell migration. Finally, we found cells expressing high levels of cxcl12 were sensitive to rapamycin in its activity inhibiting migration as well as proliferation. In summary, we found that the mTOR pathway played an important role in CXCL12/CXCR4-mediated cell migration and proposed that drugs targeting the mTOR pathway may be used for the therapy of metastatic gastric cancer expressing high levels of cxcl12.

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“…A second mechanism involves CXCL12 (also called stromal cell-derived factor 1 [SDF-1]), which binds CXCR4 and activates Akt1. This binding results in the phosphorylation of FOXO3a, a negative regulator of cell cycle progression (Wu et al 2009). The third mechanism is the one described here, where Akt is activated through TORC2.…”

Section: Evidence For Regional Differences In Nscs During Developmentmentioning

confidence: 99%

Evidence for and against regional differences in neural stem and progenitor cells of the CNS: Figure 1.

Becher¹,

Holland²

2010

Genes Dev.

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Neural stem and progenitor cells (NSCs) give rise to the cellular diversity of the CNS. There is evidence both for and against differences in these cells based on the region of the brain in which they reside. Primary brain tumors mimic many aspects of NSC behavior. Recent data suggest that some of the variability in glioma biology may be, in part, a reflection of regional differences in the NSCs from which they arise. In this issue of Genes & Development, Lee and colleagues (pp. 2317–2329) examine how NF1 regulates NSC proliferation and glial differentiation in the brainstem and cortex of the postnatal mouse brain.

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CXCL12 increases human neural progenitor cell proliferation through Akt‐1/FOXO3a signaling pathway

Cited by 106 publications

References 75 publications

Macrophage migration inhibitory factor (MIF) promotes cell survival and proliferation of neural stem/progenitor cells

Macrophage migration inhibitory factor (MIF) promotes cell survival and proliferation of neural stem/progenitor cells

Inhibition of Chemokine (CXC Motif) Ligand 12/Chemokine (CXC Motif) Receptor 4 Axis (CXCL12/CXCR4)-mediated Cell Migration by Targeting Mammalian Target of Rapamycin (mTOR) Pathway in Human Gastric Carcinoma Cells

Evidence for and against regional differences in neural stem and progenitor cells of the CNS: Figure 1.

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