title: Centrosomal abnormalities characterize human and rodent cystic cholangiocytes and are associated with Cdc25A overexpression.
abstract: Hepatic cystogenesis in polycystic liver diseases is associated with abnormalities of cholangiocyte cilia. Given the crucial association between cilia and centrosomes, we tested the hypothesis that centrosomal defects occur in cystic cholangiocytes of rodents (Pkd2(WS25/-) mice and PCK rats) and of patients with polycystic liver diseases, contributing to disturbed ciliogenesis and cyst formation. We examined centrosomal cytoarchitecture in control and cystic cholangiocytes, the effects of centrosomal abnormalities on ciliogenesis, and the role of the cell-cycle regulator Cdc25A in centrosomal defects by depleting cholangiocytes of Cdc25A in vitro and in vivo and evaluating centrosome morphology, cell-cycle progression, proliferation, ciliogenesis, and cystogenesis. The cystic cholangiocytes had atypical centrosome positioning, supernumerary centrosomes, multipolar spindles, and extra cilia. Structurally aberrant cilia were present in cystic cholangiocytes during ciliogenesis. Depletion of Cdc25A resulted in i) a decreased number of centrosomes and multiciliated cholangiocytes, ii) an increased fraction of ciliated cholangiocytes with longer cilia, iii) a decreased proportion of cholangiocytes in G1/G0 and S phases of the cell cycle, iv) decreased cell proliferation, and v) reduced cyst growth in vitro and in vivo. Our data support the hypothesis that centrosomal abnormalities in cholangiocytes are associated with aberrant ciliogenesis and that accelerated cystogenesis is likely due to overexpression of Cdc25A, providing additional evidence that pharmacological targeting of Cdc25A has therapeutic potential in polycystic liver diseases.
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Tatyana V
authors.initials: TV
authors.lastname: Masyuk
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Division of Gastroenterology, Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea.
authors.forename: Seung-Ok
authors.initials: SO
authors.lastname: Lee
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Brynn N
authors.initials: BN
authors.lastname: Radtke
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Stroope
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Bing
authors.initials: B
authors.lastname: Huang
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute-Donostia University Hospital-CIBERehd (Spanish Carlos III Health Institute), IKERBASQUE (Basque Foundation for Science) and University of Basque Country (UPV), San Sebastián, Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Banales
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Anatoliy I
authors.initials: AI
authors.lastname: Masyuk
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Splinter
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Gradilone
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Gabriella B
authors.initials: GB
authors.lastname: Gajdos
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address: larusso.nicholas@mayo.edu.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: LaRusso
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000473:pathology; D015153:Blotting, Western; D018385:Centrosome / Q000378:metabolism* / Q000648:ultrastructure*; D002923:Cilia / Q000378:metabolism / Q000648:ultrastructure; D003560:Cysts / Q000378:metabolism* / Q000648:ultrastructure*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055786:Gene Knockout Techniques; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D051381:Rats; D020687:cdc25 Phosphatases / Q000096:biosynthesis*
chemical_list: D020687:cdc25 Phosphatases