Fibroblast Growth Factor-2 and -4 Promote the Proliferation of Bone Marrow Mesenchymal Stem Cells by the Activation of the PI3K-Akt and ERK1/2 Signaling Pathways

Abstract

Bone marrow mesenchymal stem cells (BMMSCs) have the capacity for self-renewal, and differentiation into a variety of cell types. They thus represent an attractive source of material for cell therapy. However, little is known about the mechanisms underlying the proliferation of BMMSCs. The purpose of this study was to identify the factors and signaling pathways involved in the proliferation of stem cell antigen-1(+) (Sca-1(+)) BMMSCs. Among the cytokines and growth factors examined in this study, fibroblast growth factor-2 (FGF-2) and FGF-4 significantly stimulated the proliferation of Sca-1(+) BMMSCs, as determined by bromodeoxyuridine incorporation. PI3K-Akt, ERK1/2, and JAK/STAT3 pathways were investigated after stimulation with FGF-2 or FGF-4 via Western blot analysis. No changes were observed in the total ERK1/2 and Akt; however, the pERK1/2 and pAkt levels were upregulated early within 15 min in the FGF-2- or FGF-4-treated Sca-1(+) BMMSCs. Moreover, the pERK1/2 and pAkt upregulation induced by FGF-2 and -4 were completely abolished by treatment with the MEK1/2 inhibitor, U0126 and the PI3K inhibitor, LY294002. However, no change in pJAK2 or total JAK2 levels was observed in the Sca-1(+) BMMSCs induced by FGF-2 or FGF-4. As a consequence of PI3K-Akt and ERK1/2, the upregulation of c-Jun in the Sca-1(+) BMMSCs, after stimulation with FGF-2 or FGF-4, was observed after 12 and 24 h. Moreover, the activation of c-Jun in FGF-2- and FGF-4-treated Sca-1(+) BMMSCs was significantly reduced by U0126. Taken together, these data suggest that FGF-2 and -4 promote the proliferation of Sca-1(+) BMMSCs by activation of the ERK1/2 and PI3K-Akt signaling pathways.

SDF-1/CXCR4 axis modulates bone marrow mesenchymal stem cell apoptosis, migration and cytokine secretion

“…Previous studies suggested that cell survival and proliferation are mediated through activation of the signaling cascades PI3K/Akt and MAPK/ERK (Choi et al, 2008;Zhang and Cai, 2010). Our data showed that SDF-1 mediated MSC survival was associated with increased phosphorylation of Akt and ERK, which can be blocked by AMD3100 (Fig.…”

“…In agreement with our results, SDF-1 has been shown to prevent the apoptosis of hematopoietic precursors through the upregulation of Bcl-2 (Peters et al, 1998). MSCs can secrete angiogenic cytokines including bFGF and VEGF (Kinnaird et al, 2004a), both of which have been shown to inhibit cellular apoptosis (Gupta et al, 1999;Choi et al, 2008). Our study revealed that SDF-1 pretreatment increased the secretion of bFGF and VEGF by MSCs, whereas blocking of CXCR4 by AMD3100 abolished this effect (Fig.…”

Indirect co-culture with tenocytes promotes proliferation and mRNA expression of tendon/ligament related genes in rat bone marrow mesenchymal stem cells

“…It has been illustrated that growth factors such as FGF-2, FGF-4, BMP-2, EGF, PDGF, promoted the proliferation of in vitro cultured MSCs (Martin et al 1997;Liu et al 2009;Choi et al 2008;Tamama et al 2006). Meanwhile, when co-cultured with ligament cells (Mizuno et al 2008) or vascular endothelial cells (Sun et al 2007), the proliferation of MSCs was elevated which was believed due to the humoral factors released from the co-culture cells.…”

Fibroblast growth factor signaling in skeletal development and disease

“…3; Dailey et al 2005;Marie et al 2005). In early osteoblast precursor cells, activation of ERK1/2 by FGFR signaling primarily leads to increased cell proliferation (Choi et al 2008;Miraoui et al 2009). In more mature cells, ERK1/2 activation by FGF2 enhances acetylation and stabilization of RUNX2, a key transcription factor involved in osteoblastogenesis and bone formation (Xiao et al 2002;Park et al 2010;Yoon et al 2014).…”