Skip to main content

Paracrine modulation of cholangiocyte serotonin synthesis orchestrates biliary remodeling in adults.

Publication ,  Journal Article
Omenetti, A; Yang, L; Gainetdinov, RR; Guy, CD; Choi, SS; Chen, W; Caron, MG; Diehl, AM
Published in: Am J Physiol Gastrointest Liver Physiol
February 2011

Paracrine signaling between cholangiocytes and stromal cells regulates biliary remodeling. Cholangiocytes have neuroepithelial characteristics and serotonin receptor agonists inhibit their growth, but whether they are capable of serotonin biosynthesis is unknown. We hypothesized that cholangiocytes synthesize serotonin and that cross talk between liver myofibroblasts (MF) and cholangiocytes regulates this process to influence biliary remodeling. Transwell cultures of cholangiocytes ± MF, and tryptophan hydroxylase-2 knockin (TPH2KI) mice with an inactivating mutation of the neuronal tryptophan hydroxylase (TPH) isoform, TPH2, were evaluated. Results in the cell culture models confirm that cholangiocytes have serotonin receptors and demonstrate for the first time that these cells express TPH2 and produce serotonin, which autoinhibits their growth but stimulates MF production of TGF-β(1). Increased TGF-β(1), in turn, counteracts autocrine inhibition of cholangiocyte growth by repressing cholangiocyte TPH2 expression. Studies of TPH2KI mice confirm that TPH2-mediated production of serotonin plays an important role in remodeling damaged bile ducts because mice with decreased TPH2 function have reduced biliary serotonin levels and exhibit excessive cholangiocyte proliferation, accumulation of aberrant ductules and liver progenitors, and increased liver fibrosis after bile duct ligation. This new evidence that cholangiocytes express the so-called neuronal isoform of TPH, synthesize serotonin de novo, and deploy serotonin as an autocrine/paracrine signal to regulate regeneration of the biliary tree complements earlier work that revealed that passive release of serotonin from platelets stimulates hepatocyte proliferation. Given the prevalent use of serotonin-modulating drugs, these findings have potentially important implications for recovery from various types of liver damage.

Duke Scholars

Published In

Am J Physiol Gastrointest Liver Physiol

DOI

EISSN

1522-1547

Publication Date

February 2011

Volume

300

Issue

2

Start / End Page

G303 / G315

Location

United States

Related Subject Headings

  • Tryptophan Hydroxylase
  • Transforming Growth Factor beta1
  • Stem Cells
  • Serotonin
  • Regeneration
  • Receptor, Serotonin, 5-HT1A
  • Rats
  • Paracrine Communication
  • Myofibroblasts
  • Mutation
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Omenetti, A., Yang, L., Gainetdinov, R. R., Guy, C. D., Choi, S. S., Chen, W., … Diehl, A. M. (2011). Paracrine modulation of cholangiocyte serotonin synthesis orchestrates biliary remodeling in adults. Am J Physiol Gastrointest Liver Physiol, 300(2), G303–G315. https://doi.org/10.1152/ajpgi.00368.2010
Omenetti, Alessia, Liu Yang, Raul R. Gainetdinov, Cynthia D. Guy, Steve S. Choi, Wei Chen, Marc G. Caron, and Anna Mae Diehl. “Paracrine modulation of cholangiocyte serotonin synthesis orchestrates biliary remodeling in adults.Am J Physiol Gastrointest Liver Physiol 300, no. 2 (February 2011): G303–15. https://doi.org/10.1152/ajpgi.00368.2010.
Omenetti A, Yang L, Gainetdinov RR, Guy CD, Choi SS, Chen W, et al. Paracrine modulation of cholangiocyte serotonin synthesis orchestrates biliary remodeling in adults. Am J Physiol Gastrointest Liver Physiol. 2011 Feb;300(2):G303–15.
Omenetti, Alessia, et al. “Paracrine modulation of cholangiocyte serotonin synthesis orchestrates biliary remodeling in adults.Am J Physiol Gastrointest Liver Physiol, vol. 300, no. 2, Feb. 2011, pp. G303–15. Pubmed, doi:10.1152/ajpgi.00368.2010.
Omenetti A, Yang L, Gainetdinov RR, Guy CD, Choi SS, Chen W, Caron MG, Diehl AM. Paracrine modulation of cholangiocyte serotonin synthesis orchestrates biliary remodeling in adults. Am J Physiol Gastrointest Liver Physiol. 2011 Feb;300(2):G303–G315.

Published In

Am J Physiol Gastrointest Liver Physiol

DOI

EISSN

1522-1547

Publication Date

February 2011

Volume

300

Issue

2

Start / End Page

G303 / G315

Location

United States

Related Subject Headings

  • Tryptophan Hydroxylase
  • Transforming Growth Factor beta1
  • Stem Cells
  • Serotonin
  • Regeneration
  • Receptor, Serotonin, 5-HT1A
  • Rats
  • Paracrine Communication
  • Myofibroblasts
  • Mutation