Biliary exosomes influence cholangiocyte regulatory mechanisms and proliferation through interaction with primary cilia

Anatoliy I. Masyuk, Bing Q. Huang, Christopher J. Ward, Sergio A. Gradilone, Jesus M. Banales, Tatyana V. Masyuk, Brynn Radtke, Patrick L. Splinter, Nicholas F La Russo

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

Exosomes are small extracellular vesicles that are thought to participate in intercellular communication. Recent work from our laboratory suggests that, in normal and cystic liver, exosome-like vesicles accumulate in the lumen of intrahepatic bile ducts, presumably interacting with cholangiocyte cilia. However, direct evidence for exosome-ciliary interaction is limited and the physiological relevance of such interaction remains unknown. Thus, in this study, we tested the hypothesis that biliary exosomes are involved in intercellular communication by interacting with cholangiocyte cilia and inducing intracellular signaling and functional responses. Exosomes were isolated from rat bile by differential ultracentrifugation and characterized by scanning, transmission, and immunoelectron microscopy. The exosome-ciliary interaction and its effects on ERK1/2 signaling, expression of the microRNA, miR-15A, and cholangiocyte proliferation were studied on ciliated and deciliated cultured normal rat cholangiocytes. Our results show that bile contains vesicles identified as exosomes by their size, characteristic "saucer-shaped" morphology, and specific markers, CD63 and Tsg101. When NRCs were exposed to isolated biliary exosomes, the exosomes attached to cilia, inducing a decrease of the phosphorylated-to-total ERK1/2 ratio, an increase of miR-15A expression, and a decrease of cholangiocyte proliferation. All these effects of biliary exosomes were abolished by the pharmacological removal of cholangiocyte cilia. Our findings suggest that bile contains exosomes functioning as signaling nanovesicles and influencing intracellular regulatory mechanisms and cholangiocyte proliferation through interaction with primary cilia.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume299
Issue number4
DOIs
StatePublished - Oct 2010

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Exosomes
Cilia
Bile
Intrahepatic Bile Ducts
Immunoelectron Microscopy
Ultracentrifugation
MicroRNAs

Keywords

  • Bile
  • Cholangiocytes

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology
  • Medicine(all)

Cite this

Biliary exosomes influence cholangiocyte regulatory mechanisms and proliferation through interaction with primary cilia. / Masyuk, Anatoliy I.; Huang, Bing Q.; Ward, Christopher J.; Gradilone, Sergio A.; Banales, Jesus M.; Masyuk, Tatyana V.; Radtke, Brynn; Splinter, Patrick L.; La Russo, Nicholas F.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 299, No. 4, 10.2010.

Research output: Contribution to journalArticle

Masyuk, Anatoliy I. ; Huang, Bing Q. ; Ward, Christopher J. ; Gradilone, Sergio A. ; Banales, Jesus M. ; Masyuk, Tatyana V. ; Radtke, Brynn ; Splinter, Patrick L. ; La Russo, Nicholas F. / Biliary exosomes influence cholangiocyte regulatory mechanisms and proliferation through interaction with primary cilia. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2010 ; Vol. 299, No. 4.
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