Organ size is maintained by the controlled proliferation of distinct cell populations. In the mouse liver, hepatocytes in the midlobular zone that are positive for cyclin D1 (CCND1) repopulate the parenchyma at a constant rate to preserve liver mass. Here, we investigated how hepatocyte proliferation is supported by hepatic stellate cells (HSCs), pericytes that are in close proximity to hepatocytes. We used T cells to ablate nearly all HSCs in the murine liver, enabling the unbiased characterization of HSC functions. In the normal liver, complete loss of HSCs persisted for up to 10 weeks and caused a gradual reduction in liver mass and in the number of CCND1 ⁺ hepatocytes. We identified neurotrophin-3 (Ntf-3) as an HSC-produced factor that induced the proliferation of midlobular hepatocytes through the activation of tropomyosin receptor kinase B (TrkB). Treating HSC-depleted mice with Ntf-3 restored CCND1 ⁺ hepatocytes in the midlobular region and increased liver mass. These findings establish that HSCs form the mitogenic niche for midlobular hepatocytes and identify Ntf-3 as a hepatocyte growth factor.

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, exposing to the risk of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Angio-genesis is a complex process leading to the development of new vessels from pre-existing vessels. Angiogenesis is triggered by hypoxia and inflammation and is driven by the action of proangiogenic cytokines, mainly vascular endothelial growth factor (VEGF). In this review, we focus on liver angiogenesis associated with NAFLD and analyze the evidence of liver angiogenesis in animal models of NAFLD and in NAFLD patients. We also report the data explaining the role of angiogenesis in the progression of NAFLD and discuss the potential of targeting angiogenesis, notably VEGF, to treat NAFLD.

People with primary sclerosing cholangitis (PSC) have a variable and often progressive disease course that is associated with biliary and parenchymal changes. These changes are typically assessed by magnetic resonance imaging (MRI), including qualitative assessment of magnetic resonance cholangiopancreatography (MRCP). Our aim was to study the association of novel objective quantitative MRCP metrics with prognostic scores and patient outcomes. We performed a retrospective study including 77 individuals with large-duct PSC with baseline MRCP images, which were postprocessed to obtain quantitative measures of bile ducts using MRCP+™. The participants’ ANALI scores, liver stiffness by vibration-controlled transient elastography, and biochemical indices were collected at baseline. Adverse outcome-free survival was measured as the absence of decompensated cirrhosis, liver transplantation (LT), or liver-related death over a 12-year period. The prognostic value of MRCP+-derived metrics was assessed by Cox regression modelling. During a total of 386 patients-years, 16 cases of decompensation, 2 LTs, and 5 liver-related deaths were recorded. At baseline, around 50% of the patients were classified as being at risk of developing disease complications. MRCP+ metrics, particularly those describing the severity of bile duct dilatations, were correlated with all prognostic factors. Univariate analysis showed that MRCP+ metrics representing duct diameter, dilatations, and the percentage of ducts with strictures and/or dilatations were associated with survival. In a multivariable-adjusted analysis, the median duct diameter was significantly associated with survival (hazard ratio 10.9, 95% CI 1.3–90.3). MRCP+ metrics in people with PSC correlate with biochemical, elastographic, and radiological prognostic scores and are predictive of adverse outcome-free survival. In this study, we assessed in people with primary sclerosing cholangitis (PSC) the association of novel objective quantitative MRCP metrics automatically provided by a software tool (MRCP+) with prognostic scores and patient outcomes. We observed that MRCP+ metrics in people with PSC correlate with biochemical, elastographic, and radiological prognostic scores and are predictive of adverse outcome-free survival.

Both liver stiffness measurement (LSM) and biochemical response have prognostic significance in patients with primary biliary cholangitis (PBC). However, the frequency and clinical relevance of discordant biochemical and LSM changes remain unclear. We aim to determine the performance of the most recent or current LSM (LSMc) in predicting first hepatic decompensation (HD) in the setting of discordant biochemical and LSM responses. In this international, multicenter study, we included patients with at least two reliable LSM performed at least 6 months apart. Patients with prior HD, liver transplantation or hepatocellular carcinoma were excluded. Biochemical response was based on the Paris-II criteria. LSM response was defined as stable or any reduction in LSM. The primary outcome was the occurrence of the first HD. Secondary outcomes were liver transplantation and liver-related death. The influence of LSM on HD was estimated using Cox regression analysis. A total of 1,793 patients with PBC were analyzed. Over a median follow-up of 22 (IQR 12-39) months, 3.3% developed HD. Up to 55% of patients with PBC exhibited discordance between LSM and biochemical response. Among patients with LSM response, achieving Paris-II criteria was associated with a lower risk of HD (hazard ratio [HR] 0.25, 95% CI 0.06-0.97, p 10 kPa strongly predicted HD (HR 14.5, 95% CI 6.9-30.6, p <0.001), irrespective of biochemical response and prior LSM trajectories. Discordance between LSM and biochemical response is frequent. Most recent or current LSM is the strongest predictor of first liver-related events in patients with PBC, irrespective of prior biochemical response or LSM trajectory. Both liver stiffness measurement (LSM) and biochemical response have prognostic significance in patients with primary biliary cholangitis. However, the clinical relevance and how discordant biochemical and LSM changes should be best interpreted remain unclear. In this large international multicenter study, we demonstrated that once the current LSM is known, prior LSM trajectories and biochemical changes did not improve the prediction of liver-related events in patients with primary biliary cholangitis. Our finding addresses a common clinical dilemma in risk-stratifying PBC patients with discordant biochemical and LSM responses. Importantly, the use of the latest LSM value for risk prediction significantly simplifies the use of LSM in clinical decision-making for PBC patients with multiple LSM readings.