Although organ fibrosis causes significant morbidity and mortality in chronic diseases, the lack of detailed knowledge about specific cellular contributors mediating fibrogenesis hampers the design of effective anti-fibrotic therapies. Different cellular sources including tissue-resident and bone marrow-derived fibroblasts, pericytes and epithelial cells have been suggested to give rise to myofibroblasts, but their relative contributions remain controversial, with profound differences between organs and different diseases. Here we employ a novel Cre-transgenic mouse that marks 99% of hepatic stellate cells (HSCs), a liver-specific pericyte population, to demonstrate that HSCs give rise to 82-96% of myofibroblasts in models of toxic, cholestatic and fatty liver disease. Moreover, we exclude that HSCs function as facultative epithelial progenitor cells in the injured liver. On the basis of these findings, HSCs should be considered the primary cellular target for anti-fibrotic therapies across all types of liver disease.
Background & Aims Activated hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver, undergo apoptosis after cessation of liver injury, thereby contributing to the resolution of liver fibrosis. In this study, we investigated whether HSC deactivation constitutes an additional mechanism of liver fibrosis resolution. Methods HSC activation and deactivation were investigated by single cell PCR and genetic tracking in transgenic mice expressing tamoxifen-inducible CreER under control of the endogenous vimentin promoter (VimCreER). Results Single cell quantitative PCR demonstrated activation of virtually the entire HSC population in fibrotic livers, and a gradual decrease of HSC activation during fibrosis resolution, indicating deactivation of HSCs. VimCreER marked activated HSCs, demonstrated by a 6- to 16-fold induction of a membrane-bound green fluorescent protein (mGFP) Cre-reporter following injection of carbontetrachloride (CCl4) in both liver and isolated HSCs, and a shift in localization of mGFP-marked HSCs from perisinusoidal to fibrotic septa. Tracking of mGFP-positive HSCs revealed the persistence of 40–45% of mGFP expression in livers and isolated HSCs 30–45 days after cessation of CCl4, despite normalization of fibrogenesis parameters, thereby confirming reversal of HSC activation. After fibrosis resolution, mGFP expression was observed again in desmin-positive perisinusoidal HSCs; no mGFP expression was detected in hepatocytes or cholangiocytes, thereby excluding mesenchymal-epithelial transition. Notably, reverted HSCs remained in a primed state, with higher responsiveness to profibrogenic stimuli. Conclusion In mice, reversal of HSC activation contributes to the termination of fibrogenesis during fibrosis resolution but results in higher responsiveness of reverted HSCs to recurring fibrogenic stimulation.
In a retrospective analysis of 147 patients who underwent early LT (before 6 months of abstinence) for severe AH, we found that most patients survive for 1 year (94%) and 3 years (84%), similar to patients receiving liver transplants for other indications. Sustained alcohol use after LT was infrequent but associated with increased mortality. Our findings support the selective use of LT as a treatment for severe AH. Prospective studies are needed to optimize selection criteria, management of patients after LT, and long-term outcomes.
Early liver transplant (LT) for alcohol‐associated disease (i.e., without a specific sobriety period) is controversial but increasingly used. Using the multicenter American Consortium of Early Liver Transplantation for Alcoholic Hepatitis (ACCELERATE‐AH) cohort, we aimed to develop a predictive tool to identify patients pretransplant with low risk for sustained alcohol use posttransplant to inform selection of candidates for early LT. We included consecutive ACCELERATE‐AH LT recipients between 2012 and 2017. All had clinically diagnosed severe alcoholic hepatitis (AH), no prior diagnosis of liver disease or AH, and underwent LT without a specific sobriety period. Logistic and Cox regression, classification and regression trees (CARTs), and least absolute shrinkage and selection operator (LASSO) regression were used to identify variables associated with sustained alcohol use post‐LT. Among 134 LT recipients for AH with median period of alcohol abstinence pre‐LT of 54 days, 74% were abstinent, 16% had slips only, and 10% had sustained alcohol use after a median 1.6 (interquartile range [IQR]: 0.7‐2.8) years follow‐up post‐LT. Four variables were associated with sustained use of alcohol post‐LT, forming the Sustained Alcohol Use Post‐LT (SALT) score (range: 0‐11): >10 drinks per day at initial hospitalization (+4 points), multiple prior rehabilitation attempts (+4 points), prior alcohol‐related legal issues (+2 points), and prior illicit substance abuse (+1 point). The C statistic was 0.76 (95% confidence interval [CI]: 0.68‐0.83). A SALT score ≥5 had a 25% positive predictive value (95% CI: 10%‐47%) and a SALT score of <5 had a 95% negative predictive value (95% CI: 89%‐98%) for sustained alcohol use post‐LT. In internal cross‐validation, the average C statistic was 0.74. Conclusion: A prognostic score, the SALT score, using four objective pretransplant variables identifies candidates with AH for early LT who are at low risk for sustained alcohol use posttransplant. This tool may assist in the selection of patients with AH for early LT or in guiding risk‐based interventions post‐LT.
BackgroundParkinson’s disease (PD) is the most common movement neurodegenerative movement disorder. An incomplete understanding of the molecular pathways involved in its pathogenesis impedes the development of effective disease-modifying treatments. To address this gap, we have previously generated a Drosophila model of PD that overexpresses PD pathogenic mutant form of the second most common causative gene of PD, Leucine-Rich Repeat Kinase 2 (LRRK2).FindingsWe employed this model in a genetic modifier screen and identified a gene that encodes for a core subunit of retromer – a complex essential for the sorting and recycling of specific cargo proteins from endosomes to the trans-Golgi network and cell surface. We present evidence that overexpression of the Vps35 or Vps26 component of the cargo-recognition subunit of the retromer complex ameliorates the pathogenic mutant LRRK2 eye phenotype. Furthermore, overexpression of Vps35 or Vps26 significantly protects from the locomotor deficits observed in mutant LRRK2 flies, as assessed by the negative geotaxis assay, and rescues their shortened lifespan. Strikingly, overexpressing Vps35 alone protects from toxicity of rotenone, a neurotoxin commonly used to model parkinsonism, both in terms of lifespan and locomotor activity of the flies, and this protection is sustained and even augmented in the presence of mutant LRRK2. Finally, we demonstrate that knocking down expression of Vps35 in dopaminergic neurons causes a significant locomotor impairment.ConclusionsFrom these results we conclude that LRRK2 plays a role in the retromer pathway and that this pathway is involved in PD pathogenesis.
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