Hepatocyte proliferation is the principal mechanism for generating new hepatocytes in liver homeostasis and regeneration. Recent studies have suggested that this ability is not equally distributed among hepatocytes but concentrated in a small subset of hepatocytes acting like stem cells, located around the central vein or distributed throughout the liver lobule and exhibiting active WNT signaling or high telomerase activity, respectively. These findings were obtained by utilizing components of these growth regulators as markers for genetic lineage tracing. Here, we used random lineage tracing to localize and quantify clonal expansion of hepatocytes in normal and injured liver. We found that modest proliferation of hepatocytes distributed throughout the lobule maintains the hepatocyte mass and that most hepatocytes proliferate to regenerate it, with diploidy providing a growth advantage over polyploidy. These results show that the ability to proliferate is broadly distributed among hepatocytes rather than limited to a rare stem cell-like population.

Background: Hepatic cyst disease is often asymptomatic, but treatment is warranted if patients experience symptoms. We describe our management approach to these patients and review the technical nuances of the laparoscopic approach. Methods: Medical records were reviewed for operative management of hepatic cysts from 2012 to 2019 at a single, tertiary academic medical center. Results: Fifty-three patients (39 female) met the inclusion criteria with median age at presentation of 65 years. Fifty cases (94.3%) were performed laparoscopically. Fourteen patients carried diagnosis of polycystic liver disease. Dominant cyst diameter was median 129 mm and located within the right lobe (30), left lobe (17), caudate (2), or was bilobar (4). Pre-operative concern for biliary cystadenoma/cystadenocarcinoma existed for 7 patients. Operative techniques included fenestration (40), fenestration with decapitation (7), decapitation alone (3), and excision (2). Partial hepatectomy was performed in conjunction with fenestration/decapitation for 15 cases: right sided (7), left sided (7), and central (1). One formal left hepatectomy was performed in a polycystic liver disease patient. Final pathology yielded simple cyst (52) and one biliary cystadenoma. Post-operative complications included bile leak (2), perihepatic fluid collection (1), pleural effusion (1), and ascites (1). At median 7.1-month follow-up, complete resolution of symptoms occurred for 34/49 patients (69.4%) who had symptoms preoperatively. Reintervention for cyst recurrence occurred for 5 cases (9.4%). Conclusions: Outcomes for hepatic cyst disease are described with predominantly laparoscopic approach, approach with minimal morbidity, and excellent clinical results.

Transdifferentiation is a complete and stable change in cell identity that serves as an alternative to stem-cell-mediated organ regeneration. In adult mammals, findings of transdifferentiation have been limited to the replenishment of cells lost from preexisting structures, in the presence of a fully developed scaffold and niche¹. Here we show that transdifferentiation of hepatocytes in the mouse liver can build a structure that failed to form in development-the biliary system in a mouse model that mimics the hepatic phenotype of human Alagille syndrome (ALGS)². In these mice, hepatocytes convert into mature cholangiocytes and form bile ducts that are effective in draining bile and persist after the cholestatic liver injury is reversed, consistent with transdifferentiation. These findings redefine hepatocyte plasticity, which appeared to be limited to metaplasia, that is, incomplete and transient biliary differentiation as an adaptation to cell injury, based on previous studies in mice with a fully developed biliary system^3-6. In contrast to bile duct development^7-9, we show that de novo bile duct formation by hepatocyte transdifferentiation is independent of NOTCH signalling. We identify TGFβ signalling as the driver of this compensatory mechanism and show that it is active in some patients with ALGS. Furthermore, we show that TGFβ signalling can be targeted to enhance the formation of the biliary system from hepatocytes, and that the transdifferentiation-inducing signals and remodelling capacity of the bile-duct-deficient liver can be harnessed with transplanted hepatocytes. Our results define the regenerative potential of mammalian transdifferentiation and reveal opportunities for the treatment of ALGS and other cholestatic liver diseases.