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.

Nonalcoholic fatty liver disease (NAFLD) is a major health problem with complex pathogenesis. Although sex differences in NAFLD pathogenesis have been reported, the mechanisms underlying such differences remain understudied. Interleukin (IL)22 is a pleiotropic cytokine with both protective and/or pathogenic effects during liver injury. IL22 was shown to be hepatoprotective in NAFLD-related liver injury. However, these studies relied primarily on exogenous administration of IL22 and did not examine the sex-dependent effect of IL22. Here, we sought to characterize the role of endogenous IL22-receptor signaling during NAFLD-induced liver injury in males and females. We used immunofluorescence, flow cytometry, histopathologic assessment, and gene expression analysis to examine IL22 production and characterize the intrahepatic immune landscape in human subjects with NAFLD (n = 20; 11 men and 9 women) and in an in vivo Western high-fat diet–induced NAFLD model in IL22RA knock out mice and their wild-type littermates. Examination of publicly available data sets from 2 cohorts with NAFLD showed increased hepatic IL22 gene expression in females compared with males. Furthermore, our immunofluorescence analysis of liver sections from NAFLD subjects (n = 20) showed increased infiltration of IL22-producing cells in females. Similarly, IL22-producing cells were increased in wild-type female mice with NAFLD and the hepatic IL22/IL22 binding protein messenger RNA ratio correlated with expression of anti-apoptosis genes. The lack of endogenous IL22-receptor signaling (IL22RA knockout) led to exacerbated liver damage, inflammation, apoptosis, and liver fibrosis in female, but not male, mice with NAFLD. Our data suggest a sex-dependent hepatoprotective antiapoptotic effect of IL22-receptor signaling during NAFLD-related liver injury in females.

Objective: To show the underlying variability in peri‐operative mortality after radical cystectomy ( RC ) by analysing failure‐to‐rescue ( FTR ) rates, i.e. deaths after complications. Materials and Methods: Patients undergoing RC for non‐metastatic bladder cancer ( BCa ) were identified from the N ationwide I npatient S ample, 1999–2009, resulting in a weighted estimate of 79 972 patients. The FTR rates were assessed according to patient and hospital characteristics, as well as complication type. Generalized linear regression analyses were performed. Results: Overall, 26 740 patients had a complication, corresponding to a FTR rate of 5.5%. Septicaemia (odds ratio [ OR ]: 13.41, P < 0.001) and cardiac ( OR : 3.97, P < 0.001), wound‐related ( OR : 2.12, P < 0.001), genitourinary ( OR : 1.62, P = 0.045) and haematological ( OR : 1.78, P = 0.008) complications were associated with FTR . Older age ( OR : 1.05, P < 0.001), increasing comorbidities ( OR : 1.33, P < 0.001), M edicare ( OR : 1.52, P = 0.016), and M edicaid insurance status ( OR : 2.10, P = 0.029) were associated with higher odds of FTR . Conversely, increasing hospital volume ( OR : 0.992, P = 0.014) reduced the odds of FTR . Conclusions: Whereas both patient and hospital characteristics were associated with increased odds of FTR , the occurrence of septicaemia and cardiac complications were the most strongly associated with a higher risk of in‐hospital mortality.