Polarity of liver progenitor cell-derived hepatocytes determines the clinical outcome in acute-on-chronic liver failure

Background and aims:

Submassive hepatic necrosis (SMHN) is the defining histological feature, where liver progenitor cells (LPC)-mediated regeneration is crucial for recovery. We investigated LPC activation, LPC differentiation, and bile canaliculi formation following SMHN to assess their impact to recovery.

Methods:

We investigated liver tissue specimens of 55 ACLF patients with a known interval between the first symptoms of acute decompensation and the time of tissue sampling. Immunostaining for Cytokeratin 7 and CD26 was used to identify LPC and bile canaliculi.

Results:

Rapid ductular reaction occurs in all ACLF patients regardless of clinical duration and outcome, and LPC differentiated into hepatocytes over time. Newly formed hepatocytes of the three recovered ACLF patients displayed intact polarity, while in most irreversible ACLF patients, LPC-derived hepatocytes failed to form and maintain bile canaliculi, remaining hepatocytes lost polarity, and liver function deteriorated. The loss of hepatocellular polarity in irreversible ACLF was accompanied by sepsis, cholestasis, inflammation and sinusoidal fibrosis. Hepatocytes of patients with sepsis lacked apical molecules like CD26, membrane conjunction proteins such as E-Cadherin, and failed to form bile canaliculi. Systemic inflammatory response inhibited the expression of CYP7A1, the rate-limiting enzyme for bile acid synthesis, and of farnesoid X receptor, retinoid X receptor and small heterodimer partner. Over time, hepatocytes restored CYP7A1 and FXR expression, although FXR failed to translocate into the nucleus, abolishing its role as transcriptional regulator.

Conclusions:

Availability of bile canaliculi is a limiting factor for regeneration in ACLF, which is impacted by multiple local and systemic factors.