Open AccessTauroursodeoxycholic Acid, a Bile Acid, Promotes Blood Vessel Repair by Recruiting Vasculogenic Progenitor Cells
Author(s) -
Cho Jin Gu,
Lee Jun Hee,
Hong Shin Hee,
Lee Han Na,
Kim Chul Min,
Kim Seo Yoon,
Yoon Kang Jun,
Oh Bae Jun,
Kim Jae Hyeon,
Jung Seok Yoon,
Asahara Takayuki,
Kwon SangMo,
Park Sang Gyu
Publication year - 2015
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.1901
Subject(s) - tauroursodeoxycholic acid , progenitor cell , biology , cd34 , bone marrow , stem cell , immunology , microbiology and biotechnology , endoplasmic reticulum , unfolded protein response
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. S tem C ells 2015;33:792–805