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Kim J.M.,Pusan National University | Kim J.M.,Medical Research Center for Ischemic Tissue Regeneration | Cho H.H.,Pusan National University | Cho H.H.,Medical Research Center for Ischemic Tissue Regeneration | And 10 more authors.
Cellular Physiology and Biochemistry | Year: 2012

In this study, we determined the effect of TNF-α on hBMSCs proliferation as well as the role of IL-1 receptor-associated kinase 1 (IRAK1) on TNF-α signaling. Western blot analysis revealed that TNF-α treatment increased the phosphorylation of IRAK1 in hBMSCs. The downregulation of IRAK1 inhibited TNF-α-induced NF-κB activation and COX-2 expression. TNF-α treatment increased hBMSCs proliferation in a dose-dependent manner and increased ERK, JNK, and NF-κB activity. U0126, an ERK inhibitor, decreased hBMSCs proliferation and significantly blocked TNF-α-induced hBMSCs proliferation. In cells with IRAK1 or TRADD downregulation, the U0126 treatment inhibited hBMSCs proliferation and significantly suppressed TNF-α-induced hBMSCs proliferation. The downregulation of IRAK1 or TRADD inhibited TNF-α-induced ERK and JNK activation, and hBMSCs proliferation. Inhibition of NF-κB by decoy oligonucleotides reduced the TNF-α-induced hBMSCs proliferation. Immunoprecipitation analysis showed that IRAK1 does not physically interact with TNF receptor 1 (TNFR1) even in the presence of TNF-α. Suppression of IRAK1 binding protein (IRAK1BP1) inhibited TNF-α-induced increase of the proliferation and ERK1 phosphorylation of hBMSCs in the presence of TNF-α. Our data indicate that TNF-α modulates hBMSCs proliferation through ERK signaling pathways, and that IRAK1 plays an important role in TNF-α-induced NF-κB activation in hBMSCs. © 2012 S. Karger AG, Basel. Source


Heo S.C.,Medical Research Center for Ischemic Tissue Regeneration | Heo S.C.,Pusan National University | Kwon Y.W.,Medical Research Center for Ischemic Tissue Regeneration | Kwon Y.W.,Pusan National University | And 12 more authors.
Stem Cells | Year: 2014

Endothelial colony-forming cells (ECFCs) are recruited to the sites of ischemic injury in order to contribute to neovascularization and repair of injured tissues. However, therapeutic potential of ECFCs is limited due to low homing and engraftment efficiency of transplanted ECFCs. The G-protein-coupled formyl peptide receptor (FPR) 2 has been implicated in regulation of inflammation and angiogenesis, while the role of FPR2 in homing and engraftment of ECFCs and neovascularization in ischemic tissues has not been fully defined. This study was undertaken to investigate the effects of WKYMVm, a selective FPR2 agonist isolated by screening synthetic peptide libraries, on homing ability of ECFCs and vascular regeneration of ischemic tissues. WKYMVm stimulated chemotactic migration, angiogenesis, and proliferation ability of human ECFCs in vitro. Small interfering RNA-mediated silencing of FPR2, but not FPR3, abrogated WKYMVm-induced migration and angiogenesis of ECFCs. Intramuscular injection of WKYMVm resulted in attenuation of severe hind limb ischemia and promoted neovascularization in ischemic limb. ECFCs transplanted via tail vein into nude mice were incorporated into capillary vessels in the ischemic hind limb, resulting in augmented neovascularization and improved ischemic limb salvage. Intramuscular injection of WKYMVm promoted homing of exogenously administered ECFCs to the ischemic limb and ECFC-mediated vascular regeneration. Silencing of FPR2 expression in ECFCs resulted in abrogation of WKYMVm-induced in vivo homing of exogenously transplanted ECFCs to the ischemic limb, neovascularization, and ischemic limb salvage. These results suggest that WKYMVm promotes repair of ischemic tissues by stimulating homing of ECFCs and neovascularization via a FPR2-dependent mechanism. © AlphaMed Press 2013. Source


Cho H.H.,Pusan National University | Cho H.H.,Medical Research Center for Ischemic Tissue Regeneration | Shin K.K.,Pusan National University | Shin K.K.,Medical Research Center for Ischemic Tissue Regeneration | And 15 more authors.
Journal of Cellular Physiology | Year: 2010

Tumor necrosis factor-alpha (TNF-α) is a skeletal catabolic agent that stimulates osteoclastogenesis and inhibits osteoblast function. Although TNF-α inhibits the mineralization of osteoblasts, the effect of TNF-α on mesenchymal stem cells (MSC) is not clear. In this study, we determined the effect of TNF-α on osteogenic differentiation of stromal cells derived from human adipose tissue (hADSC) and the role of NF-κB activation on TNF-κ activity. TNF-κ treatment dose-dependently increased osteogenic differentiation over the first 3 days of treatment. TNF-κ activated ERK and increased NF-κB promoter activity. PDTC, an NF-κB inhibitor, blocked the osteogenic differentiation induced by TNF-α and TLR-ligands, but U102, an ERK inhibitor, did not. Overexpression of miR-146a induced the inhibition of IRAK1 expression and inhibited basal and TNF-α- and TLR ligand-induced osteogenic differentiation. TNF-α and TLR ligands increased the expression of transcriptional coactivator with PDZ-binding motif (TAZ), which was inhibited by the addition of PDTC. A ChIP assay showed that p65 was bound to the TAZ promoter. TNF-α also increased osteogenic differentiation of human gastroepiploic artery smooth muscle cells. Our data indicate that TNF-α enhances osteogenic differentiation of hADSC via the activation of NF-κB and a subsequent increase of TAZ expression. © 2010 Wiley-Liss, Inc. Source

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