Dexamethasone-dependent versus -independent markers of epithelial to mesenchymal transition in primary hepatocytes.
Recently, epithelial to mesenchymal transition (EMT) has been shown to represent a feature of dedifferentiating hepatocytes in vitro. Three-dimensional soft collagen gels can antagonize but not completely abolish this effect. Hormonal additives to culture media are known to maintain differentiated hepatocyte functions. Therefore, we studied whether insulin and dexamethasone antagonize EMT in cultured hepatocytes. Both hormones antagonized but not completely abolished certain morphological features of EMT. Dexamethasone antagonized acquisition of fibroblastoid shape, whereas insulin favored bile canaliculi formation. In a subsequent step, we analyzed expression of a battery of EMT-related genes. Of all markers tested, vimentin and snail-1 correlated best with morphological features of EMT. Interestingly, dexamethasone reduced expression levels of both vimentin and snail-1, whereas the influence of insulin was less pronounced. An important result of this study is that 12 out of 17 analyzed EMT markers were transcriptionally influenced by dexamethasone (vimentin, snail-1, snail-2, HNF4 alpha, Twist-1, ZEB2, fibronectin, occludin, MMP14, claudin-1, cytokeratin-8, and cytokeratin-18), whereas the remaining factors seemed to be less dependent on dexamethasone. In conclusion, EMT markers in hepatocytes can be classified as dexamethasone-dependent versus -independent.
Godoy
Patricio
P
Leibniz Research Center for Working Environment and Human Factors (IfADo), Ardeystrasse 67, D-44139 Dortmund, Germany. godoy@ifado.de
Lakkapamu
Sumathi
S
Schug
Markus
M
Bauer
Alexander
A
Stewart
Joanna D
JD
Bedawi
Essam
E
Hammad
Seddik
S
Amin
Jakia
J
Marchan
Rosemarie
R
Schormann
Wiebke
W
Maccoux
Lindsey
L
von Recklinghausen
Iris
I
Reif
Raymond
R
Hengstler
Jan G
JG
D000818:Animals; D054337:Cell Dedifferentiation / Q000187:drug effects* / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology*; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects; D007328:Insulin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D008858:Microscopy, Phase-Contrast; D015398:Signal Transduction / Q000187:drug effects; D014746:Vimentin / Q000502:physiology
D007328:Insulin; D014746:Vimentin; D003907:Dexamethasone