Hypoxia induces adipocyte differentiation of adipose‐derived stem cells by triggering reactive oxygen species generation

Kim, Ji Hye; Kim, Seok Ho; Song, Seung Yong; Kim, Won Serk; Song, Sun U.; Yi, TacGhee; Jeon, Myung Shin; Chung, Hyung Min; Xia, Ying; Sung, Jong Hwan

doi:10.1002/cbin.10170

Cited by 53 publications

(48 citation statements)

References 28 publications

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“…We have previously demonstrated that hypoxia significantly increases the proliferation of ASCs via NADPH oxidase 4-generated reactive oxygen species (ROS) [34,35]. Hypoxia also accelerated the adipogenic differentiation of ASCs via mitochondrial ROS generation [29]. In addition, vitamin C significantly increased ASC proliferation through the mitogen-activated protein kinase pathway and enhanced the hair-growth promoting effect of ASCs [10].…”

Section: Discussionmentioning

confidence: 99%

“…After the medium was changed to AIM, the cells were cultured for 2 weeks with MA. Oil Red O staining was used to assess the lipid accumulation in ASCs [29].…”

Section: Adipocyte Differentiationmentioning

confidence: 99%

“…The stained cells were washed twice with distilled water and examined microscopically. For quantification of Oil Red O, the cells were incubated with isopropanol for 30 minutes, and the color in the supernatant of the decolorized cells was measured by absorbance at 492 nm using a microplate reader (Tecan) [29].…”

Section: Oil Red O Stainingmentioning

confidence: 99%

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Megestrol Acetate Increases the Proliferation, Migration, and Adipogenic Differentiation of Adipose-Derived Stem Cells via Glucocorticoid Receptor

Sung

Jeong

et al. 2015

Stem Cells Translational Medicine

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Because adipose-derived stem cells (ASCs) are usually expanded to acquire large numbers of cells for therapeutic applications, it is important to increase the production yield and regenerative potential during expansion. Therefore, a tremendous need exists for alternative ASC stimuli during cultivation to increase the proliferation and adipogenic differentiation of ASCs. The present study primarily investigated the involvement of megestrol acetate (MA), a progesterone analog, in the stimulation of ASCs, and identifies the target receptors underlying stimulation. Mitogenic and adipogenic effects of MA were investigated in vitro, and pharmacological inhibition and small interfering (si) RNA techniques were used to identify the molecular mechanisms involved in the MA-induced stimulation of ASCs. MA significantly increased the proliferation, migration, and adipogenic differentiation of ASCs in a dose-dependent manner. Glucocorticoid receptor (GR) is highly expressed compared with other nuclear receptors in ASCs, and this receptor is phosphorylated after MA treatment. MA also upregulated genes downstream of GR in ASCs, including ANGPTL4, DUSP1, ERRF11, FKBP5, GLUL, and TSC22D3. RU486, a pharmacological inhibitor of GR, and transfection of siGR significantly attenuated MA-induced proliferation, migration, and adipogenic differentiation of ASCs. Although the adipogenic differentiation potential of MA was inferior to that of dexamethasone, MA had mitogenic effects in ASCs. Collectively, these results indicate that MA increases the proliferation, migration, and adipogenic differentiation of ASCs via GR phosphorylation. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:789-799 SIGNIFICANCEMagestrol acetate (MA) increases the proliferation, migration, and adipogenic differentiation of adipose-derived stem cells (ASCs) via glucocorticoid receptor phosphorylation. Therefore, MA can be applied to increase the production yield during expansion and can be used to facilitate adipogenic differentiation of ASCs.

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Section: Discussionmentioning

confidence: 99%

“…After the medium was changed to AIM, the cells were cultured for 2 weeks with MA. Oil Red O staining was used to assess the lipid accumulation in ASCs [29].…”

Section: Adipocyte Differentiationmentioning

confidence: 99%

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Megestrol Acetate Increases the Proliferation, Migration, and Adipogenic Differentiation of Adipose-Derived Stem Cells via Glucocorticoid Receptor

Sung

Jeong

et al. 2015

Stem Cells Translational Medicine

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“…Mitochondria-targeted antioxidants such as mitoCP prevent both the adipogenic differentiation and the associated increase in ROS, whereas the addition of exogenous H 2 O 2 to mitoCP-treated hMSCs rescues adipogenic differentiation [34]. Similarly, hypoxia stimulates adipocyte differentiation by enhancing the production of mitochondrial ROS [85]. On the other hand, both exogenous H 2 O 2 and oligomycin-dependent inhibition of mitochondrial activity inhibit the osteogenic differentiation of hMSCs.…”

Section: Figmentioning

confidence: 99%

Connecting Mitochondria, Metabolism, and Stem Cell Fate

Wanet

Arnould

Najimi

et al. 2015

Stem Cells and Development

260

216

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As sites of cellular respiration and energy production, mitochondria play a central role in cell metabolism. Cell differentiation is associated with an increase in mitochondrial content and activity and with a metabolic shift toward increased oxidative phosphorylation activity. The opposite occurs during reprogramming of somatic cells into induced pluripotent stem cells. Studies have provided evidence of mitochondrial and metabolic changes during the differentiation of both embryonic and somatic (or adult) stem cells (SSCs), such as hematopoietic stem cells, mesenchymal stem cells, and tissue-specific progenitor cells. We thus propose to consider those mitochondrial and metabolic changes as hallmarks of differentiation processes. We review how mitochondrial biogenesis, dynamics, and function are directly involved in embryonic and SSC differentiation and how metabolic and sensing pathways connect mitochondria and metabolism with cell fate and pluripotency. Understanding the basis of the crosstalk between mitochondria and cell fate is of critical importance, given the promising application of stem cells in regenerative medicine. In addition to the development of novel strategies to improve the in vitro lineage-directed differentiation of stem cells, understanding the molecular basis of this interplay could lead to the identification of novel targets to improve the treatment of degenerative diseases.

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“…On the other hand, P2Y 1 receptor is a heterotrimeric G-protein-coupled receptor and activates G(q) and therefore robustly promotes inositol lipid signaling responses (21). Considering that the activation of phosphoinositide-3-kinase (PI3K)-Akt pathway stimulates adipogenic differentiation (13,26), it is possible that the PI3K-Akt pathway is involved in extracellular ATP-stimulated TG accumulation via P2Y 1 receptor. Furthermore, cellsurface F 1 F 0 -ATP synthase is concentrated in lipid rafts (12,25).…”

Section: Extracellular Atp Is Responsible For the Cell-surface F 1 F mentioning

confidence: 99%

Contribution of extracellular ATP on the cell-surface F1F0-ATP synthase-mediated intracellular triacylglycerol accumulation

Kita

Arakaki

2015

Biomed. Res.

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Cell-surface F 1 F 0 -ATP synthase was involved in the cell signaling mediating various biological functions. Recently, we found that cell-surface F 1 F 0 -ATP synthase plays a role on intracellular triacylglycerol accumulation in adipocytes, and yet, the underlying mechanisms remained largely unknown. In this study, we investigated the role of extracellular ATP on the intracellular triacylglycerol accumulation. We demonstrated that significant amounts of ATP were produced extracellularly by cultured 3T3-L1 adipocytes and that the antibodies against α and β subunits of F 1 F 0 -ATP synthase inhibited the extracellular ATP production. Piceatannol, a F 1 F 0 -ATP synthase inhibitor, and apyrase, an enzyme which degrades extracellular ATP, suppressed triacylglycerol accumulation. The selective P2Y 1 receptor antagonist MRS2500 significantly inhibited triacylglycerol accumulation, whereas the selective P2X receptor antagonist NF279 has less effect. The present results indicate that cell-surface F 1 F 0 -ATP synthase on adipocytes is functional in extracellular ATP production and that the extracellular ATP produced contributes, at least in part, to the cell-surface F 1 F 0 -ATP synthase-mediated intracellular triacylglycerol accumulation in adipocytes through P2Y 1 receptor.

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Hypoxia induces adipocyte differentiation of adipose‐derived stem cells by triggering reactive oxygen species generation

Cited by 53 publications

References 28 publications

Megestrol Acetate Increases the Proliferation, Migration, and Adipogenic Differentiation of Adipose-Derived Stem Cells via Glucocorticoid Receptor

Megestrol Acetate Increases the Proliferation, Migration, and Adipogenic Differentiation of Adipose-Derived Stem Cells via Glucocorticoid Receptor

Connecting Mitochondria, Metabolism, and Stem Cell Fate

<b>Contribution of extracellular ATP on the cell-surface F</b><b><sub>1</sub></b><b>F</b><b><sub>0</sub></b><b>-ATP synthase-mediated intracellular triacylglycerol </b><b>accumulation </b>

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