Abstract
BackgroundHuman adipose-derived stem cells (hASCs) are a subset of mesenchymal stem cells (MSCs); it has been regarded as one of the most promising stem cells. We previously found that fibroblast growth factor-2 (FGF-2) enhanced the proliferation and differentiation of hASC. However, the mechanisms involved in the growth of hASCs by FGF-2 have not been investigated.MethodsHuman adipose-derived stem cells (hASCs) were cultured with FGF-2, and cell growth was assessed. Effects of FGF Receptor (FGFR) inhibitor (NVP-BGJ398), ERK1/2 inhibitor (PD98059), PI3K/Akt inhibitor (LY294002), JNK inhibitor (SP600125), and p38 MAPK inhibitor (SB203580) and Src inhibitor (PP1) on the proliferation were investigated. At the same time, we assessed the effect of FGFR inhibitor on several signaling enzymes such as ERK1/2, JNK, p38, and Akt, in protein level. The involvement of Src activation by FGF-2 was also examined.ResultsFGF-2 markedly promoted proliferation of hASCs at concentrations lower than 10 ng/ml and stimulated cell progression to the S and G2/M phases. Proliferation was blocked by the FGFR inhibitor (NVP-BGJ398) and various signaling pathway inhibitors, such as Erk1/2 inhibitor (PD98059), PI3K/Akt inhibitor (LY294002), JNK inhibitor (SP600125), and p38MAPK inhibitor (SB203580). The FGFR inhibitor reduced the activation of protein kinases, such as AKT, Erk1/2, JNK, and p38, in several signaling pathways. The downstream kinase of FGFR, Src, was activated by FGF-2, and its activation was canceled by the FGFR inhibitor. MEK1/2, a downstream kinase of Src, was parallelly regulated by FGF-2. The Src inhibitor (PP1) markedly blocked the proliferation of hASCs via inhibition of Src and MEK1/2.ConclusionSrc activation is indispensable for FGF-2-mediated proliferation of ASCs, as well as the subsequent activation of multi-signaling pathways.
Highlights
fibroblast growth factor-2 (FGF-2)-mediated proliferation of Human adipose-derived stem cells (hASCs) was suppressed by specific inhibitor of FGF Receptor (FGFR) (NVP-BGJ398, 0/0.05/0.1/1 μM) (Fig. 1c)
FGF-2 promoted cell cycle transition from G0/G1 to S When compared with the control group, flow cytometry in the FGF-2 group showed an increased trend in S and G2/M phases, and this phenomenon was inhibited in the FGF-2 with NVP-BGJ398 group (Fig. 2a)
Our results showed that proliferation of hASCs was enhanced by FGF-2 when the concentration was lower than 10 ng/ml, while an FGFR inhibitor and various signaling pathway inhibitors (Erk1/2 inhibitor, PI3K/Ak strain transforming (Akt) inhibitor, cJun N-terminal kinase (JNK) inhibitor, p38 Mitogen-activated protein kinases (MAPKs) inhibitor, and Proto-oncogene tyrosineprotein kinase Src (Src) inhibitor) inhibited FGF-2-mediated proliferation
Summary
Human adipose-derived stem cells (hASCs) were initially identified and described as a putative population of multipotent stem cells [1]. hASCs have been one of the most promising stem cells [2], the advantages of which are as follows: (1) hASCs can be ubiquitous and harvested in larger quantities without significant donor-site morbidity [3, 4]; (2) later senescence [5, 6], higherMa et al Stem Cell Research & Therapy (2019) 10:350 engineering and cell therapies in scientific and clinical research [8, 12,13,14].Fibroblast growth factor-2 (FGF-2) is one member of the FGF family, which has multiple functions such as mitogenesis, migration, morphogenesis, angiogenesis, organ development, organ regeneration, and wound healing [15]. Human adipose-derived stem cells (hASCs) were initially identified and described as a putative population of multipotent stem cells [1]. Recent studies have shown the proliferation and differentiation effects of FGF-2 on different original stem cells [16,17,18] and the proliferation effect on hASCs [19,20,21]. Zaragosi et al reported that FGF-2 plays a crucial role in differentiation and proliferation of hASCs, and that the Erk1/2 pathway is involved [20]. Our previous study found that FGF-2 increased hASC proliferation [22]; the signaling pathways activated by FGF-2 remain unexplored. We previously found that fibroblast growth factor-2 (FGF-2) enhanced the proliferation and differentiation of hASC. The mechanisms involved in the growth of hASCs by FGF-2 have not been investigated
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