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High glucose regulates cyclin D1/E of human mesenchymal stem cells through TGF‐β 1 expression via Ca 2+ /PKC/MAPKs and PI3K/Akt/mTOR signal pathways
Author(s) -
Ryu Jung Min,
Lee Min Young,
Yun Seung Pil,
Han Ho Jae
Publication year - 2010
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22091
Subject(s) - pi3k/akt/mtor pathway , protein kinase b , protein kinase c , microbiology and biotechnology , kinase , mapk/erk pathway , cell growth , p38 mitogen activated protein kinases , signal transduction , chemistry , biology , biochemistry
The elucidation of factors that support human mesenchymal stem cells (hMSCs) growth has remained unresolved partly because of the reliance of many researchers on ill‐defined, proprietary medium formulation. Thus, we investigated the effects of high glucose ( D ‐glucose, 25 mM) on hMSCs proliferation. High glucose significantly increased [ 3 H]‐thymidine incorporation and cell‐cycle regulatory protein expression levels compared with 5 mM D ‐glucose or 25 mM L ‐glucose. In addition, high glucose increased transforming growth factor‐β1 (TGF‐β 1 ) mRNA and protein expression levels. High glucose‐induced cell‐cycle regulatory protein expression levels and [ 3 H]‐thymidine incorporation, which were inhibited by TGF‐β 1 siRNA transfection and TGF‐β 1 neutralizing antibody treatment. High glucose‐induced phosphorylation of protein kinase C (PKC), p44/42 mitogen‐activated protein kinases (MAPKs), p38 MAPK, Akt, and mammalian target of rapamycin (mTOR) in a time‐dependent manner. Pretreatment of PKC inhibitors (staurosporine, 10 −6 M; bisindolylmaleimide I, 10 −6 M), LY 294002 (PI3 kinase inhibitor, 10 −6 M), Akt inhibitor (10 −5 M), PD 98059 (p44/42 MAPKs inhibitor, 10 −5 M), SB 203580 (p38 MAPK inhibitor, 10 −6 M), and rapamycin (mTOR inhibitor, 10 −8 M) blocked the high glucose‐induced cellular proliferation and TGF‐β 1 protein expression. In conclusion, high glucose stimulated hMSCs proliferation through TGF‐β 1 expression via Ca 2+ /PKC/MAPKs as well as PI3K/Akt/mTOR signal pathways. J. Cell. Physiol. 224:59–70, 2010 © 2010 Wiley‐Liss, Inc.