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World J Gastroenterol. 2010 Oct 28;16(40):5047-56.

Daily genetic profiling indicates JAK/STAT signaling promotes early hepatic stellate cell transdifferentiation.

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  • 1Department of Biology, University of North Carolina at Charlotte, Charlotte, NC 28223, USA.

Abstract

AIM:

To identify signaling pathways and genes that initiate and commit hepatic stellate cells (HSCs) to transdifferentiation.

METHODS:

Primary HSCs were isolated from male Sprague-Dawley rats and cultured on plastic for 0-10 d. Gene expression was assessed daily (quiescent to day 10 culture-activation) by real time polymerase chain reaction and data clustered using AMADA software. The significance of JAK/STAT signaling to HSC transdifferentiation was determined by treating cells with a JAK2 inhibitor.

RESULTS:

Genetic cluster analyses, based on expression of these 21 genes, showed similar expression profiles on days 1-3, days 5 and 6, and days 7-10, while freshly isolated cells (day Q) and day 4 cells were genotypically distinct from any of the other days. Additionally, gene expression clustering revealed strong upregulation of interleukin-6, JAK2 and STAT3 mRNA in the early stages of activation. Inhibition of the JAK/STAT signaling pathway impeded the morphological transdifferentiation of HSCs which correlated with decreased mRNA expression of several profibrotic genes including collagens, α-SMA, PDGFR and TGFβR.

CONCLUSION:

These data demonstrate unique clustered genetic profiles during the daily progression of HSC transdifferentiation and that JAK/STAT signaling may be critical in the early stages of transdifferentiation.

PMID:
20976841
[PubMed - indexed for MEDLINE]
PMCID:
PMC2965281
Free PMC Article
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