Tauroursodeoxycholic acid, a bile acid, promotes blood vessel repair by recruiting vasculogenic progenitor cells.

Although serum bile acid concentrations are approximately 10 µM in healthy subjects, the crosstalk between the biliary system and vascular repair has never been investigated. In this study, tauroursodeoxycholic acid (TUDCA) induced dissociation of CD34(+) hematopoietic stem cells (HSCs) from stromal cells by reducing adhesion molecule expression. TUDCA increased CD34(+) /Sca1(+) progenitors in mice peripheral blood (PB), and CD34(+) , CD31(+) , and c-kit(+) progenitors in human PB. In addition, TUDCA increased differentiation of CD34(+) HSCs into EPC lineage cells via Akt activation. EPC invasion was increased by TUDCA, which was mediated by fibroblast activating protein via Akt activation. Interestingly, TUDCA induced integration of EPCs into human aortic endothelial cells (HAECs) by increasing adhesion molecule expression. In the mouse hind limb ischemia model, TUDCA promoted blood perfusion by enhancing angiogenesis through recruitment of Flk-1(+) /CD34(+) and Sca-1(+) /c-kit(+) progenitors into damaged tissue. In GFP(+) bone marrow-transplanted hind limb ischemia, TUDCA induced recruitment of GFP(+) /c-kit(+) progenitors to the ischemic area, resulting in an increased blood perfusion ratio. Histological analysis suggested that GFP(+) progenitors mobilized from bone marrow, integrated into blood vessels, and differentiated into VEGFR(+) cells. In addition, TUDCA decreased cellular senescence by reducing levels of p53, p21, and reactive oxygen species and increased nitric oxide. Transplantation of TUDCA-primed senescent EPCs in hind limb ischemia significantly improved blood vessel regeneration, as compared with senescent EPCs. Our results suggested that TUDCA promoted neovascularization by enhancing the mobilization of stem/progenitor cells from bone marrow, their differentiation into EPCs, and their integration with preexisting endothelial cells.

ARS-interacting multi-functional protein 1 induces proliferation of human bone marrow-derived mesenchymal stem cells by accumulation of ß-catenin via fibroblast growth factor receptor 2-mediated activation of Akt.

ARS-Interacting Multi-functional Protein 1 (AIMP1) is a cytokine that is involved in the regulation of angiogenesis, immune activation, and fibroblast proliferation. In this study, fibroblast growth factor receptor 2 (FGFR2) was isolated as a binding partner of AIMP peptide (amino acids 6-46) in affinity purification using human bone marrow-derived mesenchymal stem cells (BMMSCs). AIMP1 peptide induced the proliferation of adult BMMSCs by activating Akt, inhibiting glycogen synthase kinase-3ß, and thereby increasing the level of ß-catenin. In addition, AIMP1 peptide induced the translocation of ß-catenin to the nucleus and increased the transcription of c-myc and cyclin D1 by activating the ß-catenin/T-cell factor (TCF) complex. By contrast, transfection of dominant negative TCF abolished the effect of AIMP1. The inhibition of Akt, using LY294002, abolished the accumulation and nuclear translocation of ß-catenin induced by AIMP1, leading to a decrease in c-myc and cyclin D1 expression, which decreased the proliferation of BMMSCs. An intraperitoneal injection of AIMP1 peptide into C57/BL6 mice increased the colony formation of fibroblast-like cells. Fluorescence activated cell sorting analysis showed that the colony-forming cells were CD29(+)/CD44(+)/CD90(+)/CD105(+)/CD34(-)/CD45(-), which is characteristic of MSCs. In addition, the fibroblast-like cells differentiated into adipocytes, chondrocytes, and osteocytes. Taken together, these data suggest that AIMP1 peptide promotes the proliferation of BMMSCs by activating the ß-catenin/TCF complex via FGFR2-mediated activation of Akt, which leads to an increase in MSCs in peripheral blood.

Tauroursodeoxycholate (TUDCA) inhibits neointimal hyperplasia by suppression of ERK via PKCα-mediated MKP-1 induction.

AIMS: Hyperplasia of vascular smooth muscle cells (VSMCs) after blood vessel injury is one of the major pathophysiological mechanisms associated with neointima. Tauroursodeoxycholate (TUDCA) is a cytoprotective agent in a variety of cells including hepatocytes as well as an inducer of apoptosis in cancer cells. In this study, we investigated whether TUDCA could prevent neointimal hyperplasia by suppressing the growth and migration of VSMCs. METHODS AND RESULTS: Transporters of TUDCA uptake in human VSMCs (hVSMCs) were analysed by RT-PCR and western blot. A knock-down experiment using specific si-RNA revealed that TUDCA was incorporated into hVSMCs via organic anion transporter 2 (OATP2). TUDCA reduced the viability of hVSMCs, which were mediated by inhibition of extracellular signal-regulated kinase (ERK) by induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) via protein kinase Cα (PKCα). The anti-proliferative effect of TUDCA was reversed by treatment with 7-hydroxystaurosporine, an inhibitor of PKC, and by the knock-down of MKP-1. In addition, TUDCA suppressed hVSMC migration, which was mediated by reduced matrix metalloproteinase-9 (MMP-9) expression by ERK inhibition, as well as reduced viability of hVSMCs. Rats with carotid artery balloon injury received oral administration of TUDCA; this reduced the increase in ERK and MMP-9 caused by balloon injury. TUDCA significantly decreased the ratio of intima to media by reducing proliferation and inducing apoptosis of the VSMCs. CONCLUSION: TUDCA inhibits neointimal hyperplasia by reducing proliferation and inducing apoptosis of smooth muscle cells by suppression of ERK via PKCα-mediated MKP-1 induction.

A comparison of bone generation capability in rabbits using tooth ash and plaster of Paris with platelet-rich plasma or fibrin sealant.

OBJECTIVES: Increased attention has been focused on determining the most efficacious materials for generalized bone grafts. This article presents the results of a histomorphometric analysis of bone healing in the calvaria of rabbits. The study compared the use of a tooth ash and plaster of Paris mixture alone, in association with platelet-rich plasma (PRP), and in association with fibrin sealant. STUDY DESIGN: Twelve rabbits were divided into control (group 1) and experimental groups (groups 2, 3, and 4). Group 1 was maintained as an unfilled control, and tooth ash and plaster of Paris were used in group 2, tooth ash and plaster of Paris with PRP were used in group 3, and tooth ash and plaster of Paris with fibrin sealant (Tissucol Duo Quick) were used in group 4. One-half of the animals were killed after 4 weeks, and the rest were killed after 8 weeks. Bone samples were taken from the defect areas, and newly formed bone was analyzed histomorphometrically. RESULTS: The rate of new bone formation in groups 2, 3, and 4 was significantly higher than the rate in the control group. The rate of new bone formation in groups 3 and 4 was higher than the rate in group 2, but the difference was not statistically significant. CONCLUSION: The concomitant use of PRP or fibrin sealant with tooth ash and plaster of Paris graft materials may have a positive effect on bone healing.

Comparison of genioplasty using Medpor and osteotomy.

OBJECTIVE: This retrospective study compared genioplasty using Medpor with osteotomy by measuring the amount of anteroposterior change in hard and soft tissue. STUDY DESIGN: Thirty-three patients who underwent mentum augmentation and who were followed-up >6 months were included. Subjects were divided into 2 groups: group A, with 14 patients who underwent genioplasty using osteotomy; and group B, with 19 patients who underwent genioplasty using Medpor. Patients chose one of the treatments themselves. RESULTS: The mean relapse rate of the most prominent or anterior point on the chin in the midsagittal plane of patients who went underwent osteotomy was 18.59%, and the mean relapse rate of patients who went underwent genioplasty with Medpor was 14.56%. CONCLUSIONS: It was found that the amount of the movement at the time of surgery when checked after surgery did not change in patients who underwent genioplasty using Medpor compared with patients who underwent genioplasty using osteotomy.