Centrosomal abnormalities characterize human and rodent cystic cholangiocytes and are associated with Cdc25A overexpression

Tatyana V. Masyuk, Seung Ok Lee, Brynn N. Radtke, Angela J. Stroope, Bing Huang, Jesús M. Banales, Anatoliy I. Masyuk, Patrick L. Splinter, Sergio A. Gradilone, Gabriella B. Gajdos, Nicholas F La Russo

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 (Pkd2WS25/- 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.

Original languageEnglish (US)
Pages (from-to)110-121
Number of pages12
JournalAmerican Journal of Pathology
Volume184
Issue number1
DOIs
StatePublished - Jan 2014

Fingerprint

Centrosome
Cilia
Rodentia
Cell Cycle
Cysts
Cell Cycle Resting Phase
G1 Phase
S Phase
Cell Proliferation
Pharmacology
Liver
Growth
Polycystic liver disease

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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Centrosomal abnormalities characterize human and rodent cystic cholangiocytes and are associated with Cdc25A overexpression. / Masyuk, Tatyana V.; Lee, Seung Ok; Radtke, Brynn N.; Stroope, Angela J.; Huang, Bing; Banales, Jesús M.; Masyuk, Anatoliy I.; Splinter, Patrick L.; Gradilone, Sergio A.; Gajdos, Gabriella B.; La Russo, Nicholas F.

In: American Journal of Pathology, Vol. 184, No. 1, 01.2014, p. 110-121.

Research output: Contribution to journalArticle

Masyuk, TV, Lee, SO, Radtke, BN, Stroope, AJ, Huang, B, Banales, JM, Masyuk, AI, Splinter, PL, Gradilone, SA, Gajdos, GB & La Russo, NF 2014, 'Centrosomal abnormalities characterize human and rodent cystic cholangiocytes and are associated with Cdc25A overexpression', American Journal of Pathology, vol. 184, no. 1, pp. 110-121. https://doi.org/10.1016/j.ajpath.2013.09.021
Masyuk, Tatyana V. ; Lee, Seung Ok ; Radtke, Brynn N. ; Stroope, Angela J. ; Huang, Bing ; Banales, Jesús M. ; Masyuk, Anatoliy I. ; Splinter, Patrick L. ; Gradilone, Sergio A. ; Gajdos, Gabriella B. ; La Russo, Nicholas F. / Centrosomal abnormalities characterize human and rodent cystic cholangiocytes and are associated with Cdc25A overexpression. In: American Journal of Pathology. 2014 ; Vol. 184, No. 1. pp. 110-121.
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AU - Huang, Bing

AU - Banales, Jesús M.

AU - Masyuk, Anatoliy I.

AU - Splinter, Patrick L.

AU - Gradilone, Sergio A.

AU - Gajdos, Gabriella B.

AU - La Russo, Nicholas F

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AB - 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 (Pkd2WS25/- 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.

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