Tauroursodeocycholic acid, bile acid, induces blood vessel repair Laboratory for Tracing of Gene Function Jin Gu Cho1, Shin Hee Hong1, Sang-Mo Kwon2, Sang Gyu Park1¶ 1. College of Pharmacy, Ajou University, Suwon, Gyunggido, Korea 2. Laboratory for Vascular Medicine & Stem Cell Biology, Department of Physiology, School of Medicine, Pusan National University, Yangsan, Korea Abstract Although serum bile acid concentrations are ~10 μM in healthy subjects, the cross-talk between the biliary system and vascular repair has never been investigated. In this study, 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 (FAP) via Akt activation. Interestingly, TUDCA induced integration of EPCs into human aortic endothelial cells (HAECs) by increasing adhesion molecule expression. In the mouse hindlimb 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 hindlimb 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 hindlimb 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.  Results Figure 3. TUDCA enhanced differentiation of CD34+ HSCs into EPC lineage cells.. Figure 1. TUDCA induced dissociation of CD34+ HSCs from stromal cells by reducing adhesion molecule expression. Figure 2. TUDCA induced mobilization of VPCs. Figure 4. TUDCA enhanced integration of EPCs with HAECs.. Figure 6. TUDCA promoted blood vessel regeneration in mouse hindlimb ischemia. Figure 5. TUDCA increased EPC proliferation, migration, tube formati-on, and integration with HAECs. Figure 7. TUDCA improved the vascular regeneration potential of EPCs by inhibiting cellular senescence. Discussion & Conclusion References 1. TUDCA induces dissociation of CD34+ HSCs from stromal cells by decreasing adhesion molecule expression. 2. TUDCA induces bone marrow stem cell Mobilization and differentiation into EPCs. 3. TUDCA promotes EPC integration with human aortic endothelial cells (HAECs) by increasing adhesion molecule expression. 4. TUDCA enhances EPC proliferation, invasion, and tube formation via Akt and ERK activation. 5. TUDCA enhances neovascularization in vivo. 6. TUDCA enhances EPC angiogenic activity by inhibiting senescence. ★ Tauroursodeoxycholic Acid, a Bile Acid, promotes blood vessel repair by recruiting vasculogenic progenitor cells!! 1. Carmeliet P et al. Nat Med 2003;9:653‐660. 2. Grover‐Paez F et al. Diabetes Res Clin Pract 2009;84:1‐10. 3. Asahara T et al. Circ Res 1999;85:221‐228. 4. Asahara T et al, Science 1997;275:964‐967.