High Insulin-Induced Down-Regulation of Erk-1/IGF-1R/FGFR-1 Signaling Is Required for Oxidative Stress-Mediated Apoptosis of Adipose-Derived Stem Cells

被引:23
|
作者
Scioli, Maria Giovanna [1 ]
Cervelli, Valerio [1 ]
Arcuri, Gaetano [1 ]
Gentile, Pietro [1 ]
Doldo, Elena [1 ]
Bielli, Alessandra [1 ]
Bonanno, Elena [1 ]
Orlandi, Augusto [1 ]
机构
[1] Univ Roma Tor Vergata, Dept Biomed & Prevent, I-00133 Rome, Italy
关键词
SMOOTH-MUSCLE-CELLS; PLATELET-RICH PLASMA; ADIPOCYTE DIFFERENTIATION; PREADIPOCYTE DIFFERENTIATION; LONG-TERM; RECEPTOR; TISSUE; ADIPOGENESIS; PHOSPHORYLATION; PROLIFERATION;
D O I
10.1002/jcp.24667
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Homeostasis of adipose tissue requires highly coordinated response between circulating factors and cell population. Human adult adipose-derived stem cells (ASCs) display multiple differentiation properties and are sensitive to insulin stimulation. Insulin resistance and high level of circulating insulin characterize patients with type 2 diabetes and obesity. At physiological concentration, insulin promoted proliferation and survival of ASCs in vitro, whereas high insulin level induced their dose-dependent proliferative arrest and apoptosis. Insulin-induced apoptotic commitment depended on the down-regulation of Erk-1, insulin growth factor-1 receptor (IGF-1R), and fibroblast growth factor receptor-1 (FGFR-1)-mediated signaling. Specific inhibition of Erk-1/2, IGF-1R, and FGFR activity promoted ASC apoptosis but did not increase insulin effects, whereas EGFR and ErbB2 inhibition potentiated insulin-induced apoptosis. FGFRs and EGFR inhibition reduced ASC adipogenic differentiation, whereas Erk-1/2 and IGF-1R inhibition was ineffective. Insulin-induced apoptosis associated to reactive oxygen species (ROS) accumulation and inhibition of NADPH oxidase 4 (Nox4) activity prevented ASC apoptosis. Moreover, specific inhibition of Erk-1/2, IGF-1R, and FGFR-1 activity promoted ROS generation and this effect was not cumulative with that of insulin alone. Our data indicate that insulin concentration is a critical regulatory switch between proliferation and survival of ASCs. High insulin level-induced apoptotic machinery involves Nox4-generated oxidative stress and the down-regulation of a complex receptor signaling, partially distinct from that influencing adipogenic differentiation of ASCs. J. Cell. Physiol. 229: 2077-2087, 2014. (c) 2014 Wiley Periodicals, Inc.
引用
收藏
页码:2077 / 2087
页数:11
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