title: Ischemia-induced exocytosis of Weibel-Palade bodies mobilizes stem cells.
abstract: Recruitment of various stem and progenitor cells is crucial for the regeneration of an injured organ. Levels of uric acid, one of the prototypical "alarm signals," surge after ischemia-reperfusion injury. Exogenous uric acid rapidly mobilizes endothelial progenitor cells and hematopoietic stem cells and protects the kidney from ischemia. The relatively fast responses to uric acid suggest that preformed second messengers may be released from a storage pool. Here, it is reported that monosodium urate (MSU) results in exocytosis of Weibel-Palade bodies in vitro and in vivo, leading to the release of IL-8, von Willebrand factor, and angiopoietin 2 in the culture medium or circulation. Confocal and immunoelectron microscopy confirmed depletion of von Willebrand factor in MSU-treated aortic endothelial cells. Angiopoietin 2 alone induced exocytosis of Weibel-Palade bodies, mobilized hematopoietic stem cells and depleted splenic endothelial progenitor cells, partially reproducing the actions of MSU. In addition, pretreatment with angiopoietin 2 protected the kidneys from an ischemic insult, suggesting that the previously reported renoprotection conferred by MSU likely results from exocytosis of Weibel-Palade bodies. Furthermore, experiments with toll-like receptor 4 (TLR-4)-and TLR-2-deficient mice demonstrated that uric acid-induced exocytosis of Weibel-Palade bodies is mediated by TLR-4 and that uric acid-induced release of IL-8 requires both TLR-2 and TLR-4. In summary, these results suggest that exocytosis of Weibel-Palade bodies links postischemic repair with inflammation and mobilization of stem cells.
authors: Departments of Medicine and Pharmacology, Renal Research Institute, New York Medical College, Valhalla, New York 10595, USA.
authors: Mei-Chuan
authors: MC
authors: Kuo
authors: Daniel
authors: D
authors: Patschan
authors: Susann
authors: S
authors: Patschan
authors: Leona
authors: L
authors: Cohen-Gould
authors: Hyeong-Cheon
authors: HC
authors: Park
authors: Jei
authors: J
authors: Ni
authors: Francesco
authors: F
authors: Addabbo
authors: Michael S
authors: MS
authors: Goligorsky
mesh_terms: D042702:Angiopoietin-2 / Q000378:metabolism; D002478:Cells, Cultured; D005089:Exocytosis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007511:Ischemia; D015427:Reperfusion Injury; D013234:Stem Cells / Q000166:cytology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism; D020302:Weibel-Palade Bodies / Q000378:metabolism*; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D042702:Angiopoietin-2; D016209:Interleukin-8; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014841:von Willebrand Factor; D014527:Uric Acid