TY - JOUR
T1 - Role of HIF-1α and VEGF in human mesenchymal stem cell proliferation by 17β-estradiol
T2 - Involvement of PKC, PI3K/Akt, and MAPKs
AU - Yun, Seung Pil
AU - Lee, Min Yong
AU - Ryu, Jung Min
AU - Song, Chang Hun
AU - Han, Ho Jae
PY - 2009/2
Y1 - 2009/2
N2 - 17β-Estradiol (E2) is a ste-roid 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 ≥10-10 M, significantly increased [3H]thymidine incorporation after 24 h of incubation, and E2 also increased [3H]thy- midine 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, phos- phatidylinositol 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)-1α 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-1α 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-1α activation and VEGF expression through PKC, PI3K/Akt, and MAPK pathways.
AB - 17β-Estradiol (E2) is a ste-roid 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 ≥10-10 M, significantly increased [3H]thymidine incorporation after 24 h of incubation, and E2 also increased [3H]thy- midine 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, phos- phatidylinositol 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)-1α 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-1α 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-1α activation and VEGF expression through PKC, PI3K/Akt, and MAPK pathways.
KW - Hypoxia-inducible factor-1α
KW - Mitogen-activated protein kinases
KW - Phosphatidylinositol 3-kinase
KW - Protein kinase C
KW - Vascular endothelial growth factor
UR - http://www.scopus.com/inward/record.url?scp=60849118110&partnerID=8YFLogxK
U2 - 10.1152/ajpcell.00415.2008
DO - 10.1152/ajpcell.00415.2008
M3 - Article
C2 - 18987249
AN - SCOPUS:60849118110
SN - 0363-6143
VL - 296
SP - C317-C326
JO - American Journal of Physiology - Cell Physiology
JF - American Journal of Physiology - Cell Physiology
IS - 2
ER -