| Liver Regeneration Gene Signature in Hepatitis B virus (HBV)-Associated Acute Liver Failure Identified by Gene Expression Profiling |
The liver has inherent regenerative capacity via mitotic division of mature hepatocytes. However, if the hepatic loss is massive or mature hepatocyte proliferation is impaired by chronic liver injury, HSPC are activated to support liver regeneration. Access to liver tissue from 4 patients who underwent liver transplantation for hepatitis B virus (HBV)- associated acute liver failure (ALF) provided us with the opportunity to investigate the molecular mechanisms of liver regeneration in humans by means of gene expression profiling and immunohistochemistry (IHC). Gene expression profiling of 17 liver specimens from the 4 ALF cases and individual liver specimens from 10 liver donors documented a distinct gene signature for ALF. However, unsupervised multidimensional scaling and hierarchical clustering identified two-well defined clusters that segregated according to the histopathological severity, i.e. massive hepatic necrosis (MHN; 2 patients) and submassive hepatic necrosis (SHN; 2 patients). We found that ALF is characterized by a strong hepatic stem/progenitor cell (HSPC) gene signature, as also confirmed by IHC, along with ductular reaction, both of which are more prominent in MHN. Interestingly, no evidence of further lineage differentiation was seen in MHN, whereas in SHN we detected cells with hepatocyte-like morphology. Strikingly, ALF was associated with a strong tumorigenesis gene signature. MHN had the greatest upregulation of cancer stem cell genes (EpCAM, CK19 and CK7), whereas the most upregulated genes in SHN were related to cellular growth and proliferation (AKR1B10, NQO1, RRM2, SFN, TOP2A, CCNB1, CDC20, ANLN and KI67). The extent of liver necrosis correlated with an overriding fibrogenesis gene signature, reflecting the wound healing process. Conclusion: Our data provide evidence of marked HSPC cell activation and fibrogenesis in HBV-associated ALF, which positively correlate with the extent of liver necrosis. Moreover, we detected a strong tumorigenesis gene signature in ALF, which underlines the relationship between liver regeneration and liver cancer.
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Liver samples were obtained from explanted liver of four patients with HBV-associated acute liver failure (4-5 samples per liver) and 10 individual normal liver donors and gene expression profiling was used to establish a molecular definition of this disease
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Affymetrics probeset summaries were computed using RMA algorithm. Data were then imported to BRB-ArrayTools and subsequent data filtering, median normalization and statistical analyses were performed using this software.
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| Sample ID | !Sample_title | tissue | subject | disease state |
|---|---|---|---|---|
| GSM952511 | normal liver from patient 8 | liver explant | Patient 8 | normal |
| GSM952512 | normal liver from patient 16 | liver explant | Patient 16 | normal |
| GSM952513 | normal liver from patient 18 | liver explant | Patient 18 | normal |
| GSM952514 | normal liver from patient 20 | liver explant | Patient 20 | normal |
| GSM952515 | normal liver from patient 29 | liver explant | Patient 29 | normal |
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| Sample ID | !Sample Title | Tissue | Subject | Disease state |
|---|---|---|---|---|
| GSM952511 | normal liver from patient 8 |
liver explant |
Patient 8 |
normal |
| GSM952512 | normal liver from patient 16 |
liver explant |
Patient 16 |
normal |
| GSM952513 | normal liver from patient 18 |
liver explant |
Patient 18 |
normal |
| GSM952514 | normal liver from patient 20 |
liver explant |
Patient 20 |
normal |
| GSM952515 | normal liver from patient 29 |
liver explant |
Patient 29 |
normal |
| GSM952516 | normal liver from patient 37 |
liver explant |
Patient 37 |
normal |
| GSM952517 | normal liver from patient 60 |
liver explant |
Patient 60 |
normal |
| GSM952518 | normal liver from patient 62 |
liver explant |
Patient 62 |
normal |
| GSM952519 | normal liver from patient 101 |
liver explant |
Patient 101 |
normal |
| GSM952520 | normal liver from patient 112 |
liver explant |
Patient 112 |
normal |
| GSM952521 | HBV-associated acute liver failure liver from patient 31-1 |
liver explant |
Patient 31 |
HBV-associated acute liver failure |
| GSM952522 | HBV-associated acute liver failure liver from patient 31-2 |
liver explant |
Patient 31 |
HBV-associated acute liver failure |
| GSM952523 | HBV-associated acute liver failure liver from patient 31-3 |
liver explant |
Patient 31 |
HBV-associated acute liver failure |
| GSM952524 | HBV-associated acute liver failure liver from patient 31-4 |
liver explant |
Patient 31 |
HBV-associated acute liver failure |
| GSM952525 | HBV-associated acute liver failure liver from patient 32-1 |
liver explant |
Patient 32 |
HBV-associated acute liver failure |
| GSM952526 | HBV-associated acute liver failure liver from patient 32-2 |
liver explant |
Patient 32 |
HBV-associated acute liver failure |
| GSM952527 | HBV-associated acute liver failure liver from patient 32-3 |
liver explant |
Patient 32 |
HBV-associated acute liver failure |
| GSM952528 | HBV-associated acute liver failure liver from patient 32-4 |
liver explant |
Patient 32 |
HBV-associated acute liver failure |
| GSM952529 | HBV-associated acute liver failure liver from patient 219-1 |
liver explant |
Patient 219 |
HBV-associated acute liver failure |
| GSM952530 | HBV-associated acute liver failure liver from patient 219-2 |
liver explant |
Patient 219 |
HBV-associated acute liver failure |
| GSM952531 | HBV-associated acute liver failure liver from patient 219-3 |
liver explant |
Patient 219 |
HBV-associated acute liver failure |
| GSM952532 | HBV-associated acute liver failure liver from patient 219-4 |
liver explant |
Patient 219 |
HBV-associated acute liver failure |
| GSM952533 | HBV-associated acute liver failure liver from patient 219-5 |
liver explant |
Patient 219 |
HBV-associated acute liver failure |
| GSM952534 | HBV-associated acute liver failure liver from patient 241-1 |
liver explant |
Patient 241 |
HBV-associated acute liver failure |
| GSM952535 | HBV-associated acute liver failure liver from patient 241-2 |
liver explant |
Patient 241 |
HBV-associated acute liver failure |
| GSM952536 | HBV-associated acute liver failure liver from patient 241-3 |
liver explant |
Patient 241 |
HBV-associated acute liver failure |
| GSM952537 | HBV-associated acute liver failure liver from patient 241-4 |
liver explant |
Patient 241 |
HBV-associated acute liver failure |
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