Crosstalk between HIF-1 and ROCK pathways in neuronal differentiation of mesenchymal stem cells, neurospheres and in PC12 neurite outgrowth

Pacary, Emilie; Tixier, Emmanuelle; Coulet, Florence; Roussel, Simon; Petit, Edwige; Bernaudin, Myriam

doi:10.1016/j.mcn.2007.04.002

Cited by 53 publications

(46 citation statements)

References 57 publications

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“…Consistent with recent studies on bone-marrow-derived mesenchymal stem cells (MSCs) that have indicated CoCl 2 -mediated decrease of cyclin D1 and nestin expression (Pacary et al 2007), in the present study, CoCl 2 was slightly toxic to proliferating NPCs, most likely by causing oxidative cellular damage via ROS generation. Interestingly, cobaltous ions did not harm differentiated hmNPCs, but supported both neuronal and dopaminergic differentiation.…”

Section: Discussionsupporting

confidence: 92%

Non-hypoxic Stabilization of Hypoxia-Inducible Factor Alpha (HIF-α): Relevance in Neural Progenitor/Stem Cells

et al. 2009

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Hypoxia-inducible factor-1 (HIF-1) plays an important role in neural progenitor cell (NPC) propagation and dopaminergic differentiation. In the presence of oxygen and iron, hypoxia-inducible factor 1 alpha (HIF-1alpha) is rapidly degraded via the prolyl hydroxylase (PHD)/VHL pathway. In addition to hypoxia, various non-hypoxic stimuli can stabilize HIF-1alpha in NPCs and influence the transcription of HIF-regulated genes. Here, we investigate various hypoxia mimetics: deferoxamine (DFO), ciclopirox olamine (CPX), dimethyloxallyl glycine (DMOG), a novel HIF-PHD inhibitor (FG-4497) and cobalt chloride (CoCl(2)) with respect to their ability to enhance in vitro proliferation, neurogenesis and dopaminergic differentiation of human fetal mesencephalic NPCs (hmNPCs) in ambient oxygen (21%). Although able to stabilize HIF-1alpha, iron chelators (DFO and CPX) and DMOG were toxic to hmNPCs. CoCl(2) was beneficial only towards neuronal and dopaminergic differentiation, while FG-4497 enhanced proliferation, neurogenesis and dopaminergic differentiation of hmNPCs. Both CoCl(2) and FG-4497 were protective to human dopaminergic neurons. Finally, exposure to hyperbaric oxygen (HBO) also stabilized HIF-1alpha in hmNPCs and induced neurogenesis in vitro. These findings suggest that several HIF stabilizing agents or conditions can rescue impaired neurons and promote neurogenesis in vitro.

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Section: Discussionsupporting

confidence: 92%

Non-hypoxic Stabilization of Hypoxia-Inducible Factor Alpha (HIF-α): Relevance in Neural Progenitor/Stem Cells

et al. 2009

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“…In particular, reduced RhoA-GTP level is required for neurite extension in PC12 cells [17,18]. Moreover, among the different effectors of RhoA, Rho kinases (ROCK) are believed to play a particularly important role in transducing neurite-inhibitory signals [19,20,21]. Therefore, to gain further mechanistic insight into the role of SCIRR39 in PC12 cells, we examined whether SCIRR39 affects the RhoA-ROCK pathway.…”

Section: Resultsmentioning

confidence: 99%

SCIRR39 Promotes Neurite Extension via RhoA in NGF-Induced PC12 Cells

Zhao¹,

Liu²,

Ni³

et al. 2013

Dev Neurosci

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SCIRR39 is an identified upregulated gene in rat primary neuron injury and/or regeneration process with roles largely unexplored. Using real-time quantitative PCR, Western blotting and immunofluorescence, SCIRR39 expression was detected in normal PC12 cells and upregulated in differentiated cells. The results of cell proliferation by Cell Counting Kit and cell cycle by flow cytometry indicated that SCIRR39 inhibited cell proliferation and induced the decrease in S phase. Importantly, immunofluorescent and RhoA pull-down assays showed that SCIRR39 strongly affected the neurite extension of NGF-treated PC12 cells through a RhoA-dependent mechanism, but the truncated mutants of SCIRR39 containing a truncation from 141AA to 211AA or from 397AA to 424AA failed to mock the SCIRR39 effect on neurite extension. Moreover, change of SCIRR39 expression in NGF-treated PC12 cells regulated the expression and phosphorylation of Fyn, a regulator of RhoA activity, but not the expression of ROCK II protein. Finally, immunofluorescence and RhoA pull-down assays revealed that obvious inhibition of neurite extension by SCIRR39 shRNA was reversed by RhoA inhibitor C3-transferase. Our results indicated that SCIRR39 increased the neurite extension in NGF-treated PC12 cells via RhoA, suggesting that SCIRR39 contributes to the regeneration of neuron injury by specifically altering the differentiation program.

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“…EPO has also been shown to protect retinal ganglion cells (RGCs) in rat models of glaucoma (14,15), axotomy-induced degeneration (16,17) and retinal ischemia (18) and to promote the axonal regeneration of RGCs following optic nerve transection (19). Previous studies also showed that there is crosstalk between hypoxia inducible factor-1 (HIF-1) and the ROCK pathways in neuronal differentiation of mesenchymal stem cells, neurospheres and in PC12 neurite outgrowth (20), and that EPO is one of the major target genes of HIF-1. Therefore, crosstalk may also exist between EPO and the RhoA/ROCK pathway.…”

Section: Introductionmentioning

confidence: 99%

The effects of erythropoietin on RhoA/Rho-associated kinase expression in rat retinal explants cultured with glutamate

Huang

Wang

Shen

et al. 2012

Molecular Medicine Reports

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Abstract. The aim of this study was to investigate the effects of erythropoietin (EPO) on RhoA/Rho-associated kinase (ROCK) expression in rat retinal explants cultured with glutamate. After the retinal explants were cultured in serumfree R16 nutrient medium for 24 h, the retinal explants were divided into control (R16 nutrient medium), glutamate (R16 nutrient medium containing 5 mM/l glutamate) and glutamate + EPO (R16 nutrient medium containing 5 mM/l glutamate and 6.0 U/ml EPO) groups, and culturing was continued for another 72 h. The mRNA and protein expression of total RhoA, ROCK1 and ROCK2 in the retinal explants was examined by RT-PCR and western blotting, and active RhoA in the retinal explants was detected via GST-RBD binding and immunoblotting with an antibody specific to active RhoA. The total RhoA mRNA and protein expression did not differ substantially between the control, the glutamate and the glutamate + EPO groups. The glutamate increased the active RhoA, ROCK1 and ROCK2 expression in cultured retinal explants (P<0.05), whereas the expression of active RhoA, ROCK1 and ROCK2 in the glutamate + EPO group was significantly lower than that in the simple glutamate group (P<0.05) and similar to that in the control group. In conclusion, EPO downregulates active RhoA, ROCK1 and ROCK2 expression in retinal explants cultured with glutamate.

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Crosstalk between HIF-1 and ROCK pathways in neuronal differentiation of mesenchymal stem cells, neurospheres and in PC12 neurite outgrowth

Cited by 53 publications

References 57 publications

Non-hypoxic Stabilization of Hypoxia-Inducible Factor Alpha (HIF-α): Relevance in Neural Progenitor/Stem Cells

Non-hypoxic Stabilization of Hypoxia-Inducible Factor Alpha (HIF-α): Relevance in Neural Progenitor/Stem Cells

SCIRR39 Promotes Neurite Extension via RhoA in NGF-Induced PC12 Cells

The effects of erythropoietin on RhoA/Rho-associated kinase expression in rat retinal explants cultured with glutamate

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