Role of FAK phosphorylation in hypoxia-induced hMSCS migration: involvement of VEGF as well as MAPKS and eNOS pathways

Lee, Yu Jin; Song, Chang Hun; Ahn, Young Keun; Han, Ho Jae

doi:10.1152/ajpcell.00418.2009

Cited by 55 publications

(45 citation statements)

References 36 publications

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“…In vascular smooth muscle cells, HIF-1α expression decreased cell migration and adherence to the ECM, with no evident changes in vincullin or focal adhesion kinase (FAK) localisation [34]. Hypoxia increased MSC migration, probably via VEGF-mediated phosphorylation of FAK and activation of MAPK and eNOS signalling [35]. Hypoxia increased αvβ3 integrin cell surface expression and cell adhesion in trophoblast stem cells [36].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-induced responses by endothelial colony-forming cells are modulated by placental growth factor

et al. 2016

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BackgroundEndothelial colony-forming cells (ECFCs), also termed late outgrowth endothelial cells, are a well-defined circulating endothelial progenitor cell type with an established role in vascular repair. ECFCs have clear potential for cell therapy to treat ischaemic disease, although the precise mechanism(s) underlying their response to hypoxia remains ill-defined.MethodsIn this study, we isolated ECFCs from umbilical cord blood and cultured them on collagen. We defined the response of ECFCs to 1% O2 exposure at acute and chronic time points.ResultsIn response to low oxygen, changes in ECFC cell shape, proliferation, size and cytoskeleton phenotype were detected. An increase in the number of senescent ECFCs also occurred as a result of long-term culture in 1% O2. Low oxygen exposure altered ECFC migration and tube formation in Matrigel®. Increases in angiogenic factors secreted from ECFCs exposed to hypoxia were also detected, in particular, after treatment with placental growth factor (PlGF). Exposure of cells to agents that stabilise hypoxia-inducible factors such as dimethyloxalylglycine (DMOG) also increased PlGF levels. Conditioned medium from both hypoxia-treated and DMOG-treated cells inhibited ECFC tube formation. This effect was reversed by the addition of PlGF neutralising antibody to the conditioned medium, confirming the direct role of PlGF in this effect.ConclusionsThis study deepens our understanding of the response of ECFCs to hypoxia and also identifies a novel and important role for PlGF in regulating the vasculogenic potential of ECFCs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0430-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Hypoxia-induced responses by endothelial colony-forming cells are modulated by placental growth factor

et al. 2016

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“…By contrast, ROS at low levels function as signaling molecules to enhance the proliferation and migration of stem cells by serving as second messengers for signal transduction and by triggering the expression of early response genes, such as Akt and ERK1/2, as well as the activation of tyrosine kinases and the deactivation of tyrosine phosphatases [25,26]. Further, ROS are reportedly involved in the secretion of diverse growth factors (ie, vascular endothelial growth factor) from stem cells by stabilizing the HIF-1a levels [23,32,33]. This evidence suggests that the controlled production of ROS by hypoxia has a beneficial effect on the cellular homeostasis of ASCs.…”

Section: Discussionmentioning

confidence: 99%

“…Wang et al reported the signal pathway involved in the growth factor secretion of mesenchymal stem cells, and that hypoxia-induced secretion was associated with increased activation of p38 mitogenactivated protein kinase [22]. In addition, involvement of phosphatidylinositol 3 kinase/Akt, a mammalian target for rapamycin, focal adhesion kinase, and Src phosphorylation has been demonstrated in the hypoxia-induced proliferation and migration of embryonic stem cells [23]. It is unknown, however, if they are involved in an acute response to hypoxia and in the stimulation of ASCs.…”

Section: Introductionmentioning

confidence: 99%

The Pivotal Role of Reactive Oxygen Species Generation in the Hypoxia-Induced Stimulation of Adipose-Derived Stem Cells

Kim

Park

et al. 2011

Stem Cells and Development

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Adipose-derived stem cells (ASCs) offer a potential alternative for tissue repair and regeneration. We have recently shown that hypoxia stimulates ASCs and enhances the regenerative potential of ASCs, which is beneficial for ASC therapy. In the present study, we further investigated a key mediator and a signal pathway involved in the stimulation of ASC during hypoxia. Culturing ASC in a hypoxic incubator (2% oxygen tension) increased the proliferation and migration, and this was mediated by Akt and ERK pathways. To determine the generation of reactive oxygen species (ROS), 2¢,7¢-dichlorofluorescin diacetate intensity was detected by fluorescence-activated cell sorting. Hypoxia significantly increased the dichlorofluorescin diacetate intensity, which was greatly reduced by N-acetyl-cysteine and diphenyleneiodonium treatment. Likewise, the hypoxia-induced proliferation and migration of ASCs were reversed by N-acetyl-cysteine and diphenyleneiodonium treatment, suggesting the involvement of ROS generation in ASC stimulation. Further, we examined the activation of receptor tyrosine kinases and observed that hypoxia stimulated the phosphorylation of platelet-derived growth factor receptor-b. In summary, the ROS produced by ASCs in response to hypoxia was mostly likely due to NADPH oxidase activity. The increased cellular ROS was accompanied by the phosphorylation of platelet-derived growth factor receptor-b as well as by the activation of ERK and Akt signal pathways. Our results suggest a pivotal role for ROS generation in the stimulation of ASCs by hypoxia.

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“…(C) Protein levels of MMP9, MMP12 and MMP16 in lysates and cell culture supernatants of UCB-MSCs treated with 1 μM H2O2 for 12 or 24 h were determined by Western blot analysis. ESC lysate is positive control of MMP9 (Lee et al, 2010b). (D) Expression of MMP12 (green) was determined by confocal microscopy using immunofluorescence staining.…”

Section: Figurementioning

confidence: 99%

Reactive oxygen species induce MMP12‐dependent degradation of collagen 5 and fibronectin to promote the motility of human umbilical cord‐derived mesenchymal stem cells

Yun

Lee

et al. 2014

British J Pharmacology

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Background and PurposeReactive oxygen species (ROS) are potent regulators of stem cell behaviour; however, their physiological significance as regards MMP‐mediated regulation of the motility of human umbilical cord blood‐derived mesenchymal stem cells (UCB‐MSCs) has not been characterized. In the present study, we investigated the role of hydrogen peroxide (H2O2) and associated signalling pathways in promoting UCB‐MSCs motility.Experimental ApproachThe regulatory effects of H2O2 on the activation of PKC, MAPKs, NF‐κB and β‐catenin were determined. The expressions of MMP and extracellular matrix proteins were examined. Pharmacological inhibitors and gene‐specific siRNA were used to identify the signalling pathways of H2O2 that affect UCB‐MSCs motility. An experimental skin wound‐healing model was used to confirm the functional role of UCB‐MSCs treated with H2O2 in ICR mice.Key ResultsH2O2 increased the motility of UCB‐MSCs by activating PKCα via a calcium influx mechanism. H2O2 activated ERK and p38 MAPK, which are responsible for the distinct activation of transcription factors NF‐κB and β‐catenin. UCB‐MSCs expressed eight MMP genes, but only MMP12 expression was uniquely regulated by NF‐κB and β‐catenin activation. H2O2 increased the MMP12‐dependent degradation of collagen 5 (COL‐5) and fibronectin (FN) associated with UCB‐MSCs motility. Finally, topical transplantation of UCB‐MSCs treated with H2O2 enhanced skin wound healing in mice.Conclusions and ImplicationsH2O2 stimulated UCB‐MSCs motility by increasing MMP12‐dependent degradation of COL‐5 and FN through the activation of NF‐κB and glycogen synthase kinase‐3β/β‐catenin, which is critical for providing a suitable microenvironment for MSCs transplantation and re‐epithelialization of skin wounds in mice.

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Role of FAK phosphorylation in hypoxia-induced hMSCS migration: involvement of VEGF as well as MAPKS and eNOS pathways

Cited by 55 publications

References 36 publications

Hypoxia-induced responses by endothelial colony-forming cells are modulated by placental growth factor

Hypoxia-induced responses by endothelial colony-forming cells are modulated by placental growth factor

The Pivotal Role of Reactive Oxygen Species Generation in the Hypoxia-Induced Stimulation of Adipose-Derived Stem Cells

Reactive oxygen species induce MMP12‐dependent degradation of collagen 5 and fibronectin to promote the motility of human umbilical cord‐derived mesenchymal stem cells

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