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RECEPTORS AND SIGNAL TRANSDUCTION

Role of HIF-1 and VEGF in human mesenchymal stem cell proliferation by 17β-estradiol: involvement of PKC, PI3K/Akt, and MAPKs

¹Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University; and ²JB Stem Cell Institute, Incorporated, College of Medicine, Chosun University, Gwangju, Korea

Submitted 9 August 2008 ; accepted in final form 31 October 2008

17β-Estradiol (E₂) is a steroid hormone well known for its roles in the regulation of various cell functions. However, the precise role that E₂ plays in the proliferation of human mesenchymal stem cells (hMSCs) has not been completely elucidated. In the present study, we examined the effects of E₂ on cell proliferation and the related signaling pathways using hMSCs. We showed that E₂, at 10^–9 M, significantly increased [³H]thymidine incorporation after 24 h of incubation, and E₂ also increased [³H]thymidine incorporation at >6 h. Also, E₂ significantly increased the percentage of the cell population in the S phase based on FACS analysis. Moreover, E₂ increased estrogen receptor (ER), PKC, phosphatidylinositol 3-kinase (PI3K)/Akt, and MAPK phosphorylation. Subsequently, these signaling molecules were involved in an E₂-induced increase of [³H]thymidine incorporation. E₂ also increased hypoxia-inducible factor (HIF)-1 and VEGF protein levels. These levels of protein expression were inhibited by ICI-182,780 (10^–6 M, an ER antagonist), staurosporine and bisindolylmaleimide I (10^–6 M, a PKC inhibitor), LY-294002 (10^–6 M, a PI3K inhibitor), Akt inhibitor (10^–5 M), SP-600125 (10^–6 M, a SAPK/JNK inhibitor), and PD-98059 (10^–5 M, a p44/42 MAPKs inhibitor). In addition, HIF-1 small interfering (si)RNA and ICI-182,780 inhibited E₂-induced VEGF expression and cell proliferation. VEGF siRNA also significantly inhibited E₂-induced cell proliferation. In conclusion, E₂ partially stimulated hMSC proliferation via HIF-1 activation and VEGF expression through PKC, PI3K/Akt, and MAPK pathways.

mitogen-activated protein kinases; hypoxia-inducible factor-1; vascular endothelial growth factor; protein kinase C; phosphatidylinositol 3-kinase

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