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Analysis of epithelial-mesenchymal transition markers in the histogenesis of hepatic progenitor cell in HBV-related liver diseases

View Article: PubMed Central - PubMed

ABSTRACT

Background: The origin and heterogeneity of hepatic progenitor cells (HPCs) remain unclear. This study aimed to investigate the involvement of epithelial-mesenchymal transition (EMT) in the histogenesis of HPCs.

Methods: Surgical liver specimens from patients with HBV-related hepatitis and cirrhosis were investigated with double immunofluorescence labeling to detect antigens associated with HPCs and EMT. Ductular reactions were subjected to quantitative reverse transcription PCR following isolation by laser capture microdissection. Electron microscopic examination was performed to find an ultrastructural evidence of EMT.

Results: The number of EpCAM-positive HPCs was proportional to the disease severity. The S100A4 expression of HPCs was firstly observed in mild hepatitis and increased significantly in moderate hepatitis, but decreased in severe hepatitis and cirrhosis. The levels of MMP-2, Twist, and Snail increased in direct proportion to the number of HPCs. Some hepatocytes adjacent to portal tracts in cirrhosis showed positivity for MMP-2. Although CK7 and E-cadherin levels decreased in mild and moderate hepatitis, HPCs re-expressed both of them in severe hepatitis and cirrhosis. However, HPCs expressed neither vimentin nor αSMA. The relative mRNA expression levels of EpCAM and EMT-associated markers supported immunohistochemical results. Electron microscopic examination demonstrated the existence of intercellular junctions among HPCs, cholangiocytes, and intermediate hepatocyte-like cells.

Conclusion: We provided preliminary evidence for the involvement of EMT in the histogenesis of HPCs from cholangiocytes in HBV-related liver diseases. HPCs may re-transdifferentiate into hepatocytes, and the differentiation direction depends, at least in part, on interactions between HPCs and the surrounding microenvironment, especially the non-resolving inflammation caused by HBV infection.

No MeSH data available.


Related in: MedlinePlus

The expressions of CK7 and E-cadherin in HPCs. a, f Cholangiocytes in normal liver exhibited positivity for CK7 and E-cadherin rather than EpCAM (original magnification × 200). b, g HPCs within DRs of mild hepatitis co-expressed CK7 and EpCAM. The down-regulated expression of E-cadherin was detected in DRs of cirrhosis (original magnification × 200). c, h The number of CK7- or E-cadherin-positivity HPCs decreased significantly in moderate hepatitis (original magnification × 200). d, i In sections of severe hepatitis, the number of CK7- or E-cadherin-positivity HPCs increased (original magnification × 200). e, j Majority of HPCs within DRs of cirrhosis re-expressed CK7 or E-cadherin (original magnification × 200). k, p Cholangiocytes and hepatocytes in the normal liver did not express Twist and Snail (original magnification × 200). l-o Twist-positive HPCs numbers increased in direct proportion to disease severity (original magnification × 200). q-t Hepatitis and cirrhosis resulted in the elevated level of Snail (original magnification × 200)
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Fig2: The expressions of CK7 and E-cadherin in HPCs. a, f Cholangiocytes in normal liver exhibited positivity for CK7 and E-cadherin rather than EpCAM (original magnification × 200). b, g HPCs within DRs of mild hepatitis co-expressed CK7 and EpCAM. The down-regulated expression of E-cadherin was detected in DRs of cirrhosis (original magnification × 200). c, h The number of CK7- or E-cadherin-positivity HPCs decreased significantly in moderate hepatitis (original magnification × 200). d, i In sections of severe hepatitis, the number of CK7- or E-cadherin-positivity HPCs increased (original magnification × 200). e, j Majority of HPCs within DRs of cirrhosis re-expressed CK7 or E-cadherin (original magnification × 200). k, p Cholangiocytes and hepatocytes in the normal liver did not express Twist and Snail (original magnification × 200). l-o Twist-positive HPCs numbers increased in direct proportion to disease severity (original magnification × 200). q-t Hepatitis and cirrhosis resulted in the elevated level of Snail (original magnification × 200)

Mentions: In normal liver, DRs were absent and cholangiocytes in intrahepatic bile duct showed positivity for CK7 and E-cadherin (Figs. 1a, and 2a, f). They did not express EpCAM or EMT-associated markers (Figs. 1f, k and 2k, 2p).Fig. 1


Analysis of epithelial-mesenchymal transition markers in the histogenesis of hepatic progenitor cell in HBV-related liver diseases
The expressions of CK7 and E-cadherin in HPCs. a, f Cholangiocytes in normal liver exhibited positivity for CK7 and E-cadherin rather than EpCAM (original magnification × 200). b, g HPCs within DRs of mild hepatitis co-expressed CK7 and EpCAM. The down-regulated expression of E-cadherin was detected in DRs of cirrhosis (original magnification × 200). c, h The number of CK7- or E-cadherin-positivity HPCs decreased significantly in moderate hepatitis (original magnification × 200). d, i In sections of severe hepatitis, the number of CK7- or E-cadherin-positivity HPCs increased (original magnification × 200). e, j Majority of HPCs within DRs of cirrhosis re-expressed CK7 or E-cadherin (original magnification × 200). k, p Cholangiocytes and hepatocytes in the normal liver did not express Twist and Snail (original magnification × 200). l-o Twist-positive HPCs numbers increased in direct proportion to disease severity (original magnification × 200). q-t Hepatitis and cirrhosis resulted in the elevated level of Snail (original magnification × 200)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC5121942&req=5

Fig2: The expressions of CK7 and E-cadherin in HPCs. a, f Cholangiocytes in normal liver exhibited positivity for CK7 and E-cadherin rather than EpCAM (original magnification × 200). b, g HPCs within DRs of mild hepatitis co-expressed CK7 and EpCAM. The down-regulated expression of E-cadherin was detected in DRs of cirrhosis (original magnification × 200). c, h The number of CK7- or E-cadherin-positivity HPCs decreased significantly in moderate hepatitis (original magnification × 200). d, i In sections of severe hepatitis, the number of CK7- or E-cadherin-positivity HPCs increased (original magnification × 200). e, j Majority of HPCs within DRs of cirrhosis re-expressed CK7 or E-cadherin (original magnification × 200). k, p Cholangiocytes and hepatocytes in the normal liver did not express Twist and Snail (original magnification × 200). l-o Twist-positive HPCs numbers increased in direct proportion to disease severity (original magnification × 200). q-t Hepatitis and cirrhosis resulted in the elevated level of Snail (original magnification × 200)
Mentions: In normal liver, DRs were absent and cholangiocytes in intrahepatic bile duct showed positivity for CK7 and E-cadherin (Figs. 1a, and 2a, f). They did not express EpCAM or EMT-associated markers (Figs. 1f, k and 2k, 2p).Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

Background: The origin and heterogeneity of hepatic progenitor cells (HPCs) remain unclear. This study aimed to investigate the involvement of epithelial-mesenchymal transition (EMT) in the histogenesis of HPCs.

Methods: Surgical liver specimens from patients with HBV-related hepatitis and cirrhosis were investigated with double immunofluorescence labeling to detect antigens associated with HPCs and EMT. Ductular reactions were subjected to quantitative reverse transcription PCR following isolation by laser capture microdissection. Electron microscopic examination was performed to find an ultrastructural evidence of EMT.

Results: The number of EpCAM-positive HPCs was proportional to the disease severity. The S100A4 expression of HPCs was firstly observed in mild hepatitis and increased significantly in moderate hepatitis, but decreased in severe hepatitis and cirrhosis. The levels of MMP-2, Twist, and Snail increased in direct proportion to the number of HPCs. Some hepatocytes adjacent to portal tracts in cirrhosis showed positivity for MMP-2. Although CK7 and E-cadherin levels decreased in mild and moderate hepatitis, HPCs re-expressed both of them in severe hepatitis and cirrhosis. However, HPCs expressed neither vimentin nor αSMA. The relative mRNA expression levels of EpCAM and EMT-associated markers supported immunohistochemical results. Electron microscopic examination demonstrated the existence of intercellular junctions among HPCs, cholangiocytes, and intermediate hepatocyte-like cells.

Conclusion: We provided preliminary evidence for the involvement of EMT in the histogenesis of HPCs from cholangiocytes in HBV-related liver diseases. HPCs may re-transdifferentiate into hepatocytes, and the differentiation direction depends, at least in part, on interactions between HPCs and the surrounding microenvironment, especially the non-resolving inflammation caused by HBV infection.

No MeSH data available.


Related in: MedlinePlus