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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.
AuthorsJin Gu Cho, Jun Hee Lee, Shin Hee Hong, Han Na Lee, Chul Min Kim, Seo Yoon Kim, Kang Jun Yoon, Bae Jun Oh, Jae Hyeon Kim, Seok Yoon Jung, Takayuki Asahara, Sang-Mo Kwon, Sang Gyu Park
JournalStem cells (Dayton, Ohio) (Stem Cells) Vol. 33 Issue 3 Pg. 792-805 (Mar 2015) ISSN: 1549-4918 [Electronic] England
PMID25407160 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2014 AlphaMed Press.
Chemical References
  • Taurochenodeoxycholic Acid
  • ursodoxicoltaurine
Topics
  • Adult
  • Animals
  • Blood Vessels (cytology, drug effects)
  • Cell Differentiation (physiology)
  • Endothelial Cells (cytology, metabolism)
  • Female
  • Hematopoietic Stem Cells (cytology, metabolism)
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neovascularization, Pathologic (pathology)
  • Stem Cells (cytology, drug effects, metabolism)
  • Taurochenodeoxycholic Acid (pharmacology)

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