Background and aims:
Given the shortage of donor livers, only patients with MELD score > 15 are on the waiting list for liver transplantation. Impressively, a large portion of patients display successful hepatic regeneration in the explanted livers. This raises an issue whether these patients should obtain donor livers. Here, we examined how regenerative hepatocytes can restore liver function and rescue patients from acute-on-chronic liver failure (ACLF).
Methods:
Twenty-five ACLF patients (17 received liver transplantation while 8 recovered spontaneously) with liver tissue examination were enrolled. Clinical, blood biochemical and liver histological parameters were analyzed. An in vitro liver progenitor cells (LPC)-to-hepatocytes model was used for mechanistic investigations. ChIP and Co-IP were used to clarify binding between protein/DNA and proteins.
Results:
Successful LPC-mediated hepatic regeneration was present in all ACLF patients, regardless of clinic outcome. In contrast to recovered ACLF patients, regenerative hepatocytes in irreversible patients did not provide sufficient hepatic function and showed worsened international normalized rate (INR) and serum total bilirubin levels, the two parameters defining MELD score. Hepatocytes of these patients lacked HNF4a, a core hepatic transcription factor, which owns multiple binding sites for coagulation factors. Expression of HNF4a in LPC-derived hepatocytes required two transcription factor complexes, TRIM33-SMAD2/3 and FOXH1-SMAD2/3/4, which were driven by an extracellular Activin signal. In contrast to irreversible patients, recovered ACLF patients demonstrated robust expression of components of these transcription factor complexes and HNF4a in nuclei of hepatocytes.
Conclusions:
These results explain why MELD score is an excellent tool for predicting prognosis of patients with end-stage liver diseases and allocation of donor liver. In the future, establishing a novel scoring system comprising MELD score, serum Activin levels and liver HNF4a expression may improve prediction for outcome of ACLF.
