title: Tauroursodeoxycholic acid, a bile acid, promotes blood vessel repair by recruiting vasculogenic progenitor cells.
abstract: 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.
authors.affiliation: Department of Biomedical Science, CHA University, Sungnamsi, Gyunggido, Korea.
authors.forename: Jin Gu
authors.initials: JG
authors.lastname: Cho
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Shin Hee
authors.initials: SH
authors.lastname: Hong
authors.forename: Han Na
authors.initials: HN
authors.lastname: Lee
authors.forename: Chul Min
authors.initials: CM
authors.lastname: Kim
authors.forename: Seo Yoon
authors.initials: SY
authors.lastname: Kim
authors.forename: Kang Jun
authors.initials: KJ
authors.lastname: Yoon
authors.forename: Bae Jun
authors.initials: BJ
authors.lastname: Oh
authors.forename: Jae Hyeon
authors.initials: JH
authors.lastname: Kim
authors.forename: Seok Yoon
authors.initials: SY
authors.lastname: Jung
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asahara
authors.forename: Sang-Mo
authors.initials: SM
authors.lastname: Kwon
authors.forename: Sang Gyu
authors.initials: SG
authors.lastname: Park
mesh_terms: D000328:Adult; D000818:Animals; D001808:Blood Vessels / Q000166:cytology* / Q000187:drug effects*; D002454:Cell Differentiation / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000473:pathology; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*
chemical_list: D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine
keywords: Endothelial colony forming cells; Hematopoietic stem cell; Tauroursodeoxycholic acid