Dataset Information

Human Allogeneic Liver-Derived Progenitor Cells Significantly Improve NAFLD Activity Score and Fibrosis in Late-Stage NASH Animal Model.

ABSTRACT: Accumulated experimental and clinical evidence supports the development of human allogeneic liver-derived progenitor cells (HALPCs) to treat fibro-inflammatory liver diseases. The aim of the present study was to evaluate their therapeutic effect in a non-alcoholic steatohepatitis (NASH)-STAM mouse model. The immune signaling characteristics of HALPCs were first assessed in vitro. Upon inflammation treatment, HALPCs secreted large amounts of potent bioactive prostaglandin E2 and indoleamine 2,3-dioxygenase, which significantly reduced CD4⁺ T-lymphocyte proliferation and secretion of proinflammatory cytokines. In vivo, HALPCs were intravenously administered as single or triple shots (of a dose of 12.5 × 10⁶ cells/kg BW) in STAM mice. Transplantation of HALPCs was associated with a significant decrease in the NAFLD activity score at an early stage and in both inflammation and hepatocyte ballooning scores in late-stage NASH. Sirius red staining analyses revealed decreased collagen deposition in the pericentral region at both stages of NASH. Altogether, these findings showed the anti-inflammatory and anti-fibrotic features of HALPCs in an in vivo NASH model, which suggests their potential to reverse the progression of this chronic fibro-inflammatory disease.

SUBMITTER: Najimi M

PROVIDER: S-EPMC9497074 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Human Allogeneic Liver-Derived Progenitor Cells Significantly Improve NAFLD Activity Score and Fibrosis in Late-Stage NASH Animal Model.

Najimi Mustapha M Michel Sébastien S Binda Maria M MM Gellynck Kris K Belmonte Nathalie N Mazza Giuseppe G Gordillo Noelia N Vainilovich Yelena Y Sokal Etienne E

Cells 20220913 18

Accumulated experimental and clinical evidence supports the development of human allogeneic liver-derived progenitor cells (HALPCs) to treat fibro-inflammatory liver diseases. The aim of the present study was to evaluate their therapeutic effect in a non-alcoholic steatohepatitis (NASH)-STAM mouse model. The immune signaling characteristics of HALPCs were first assessed in vitro. Upon inflammation treatment, HALPCs secreted large amounts of potent bioactive prostaglandin E2 and indoleamine 2,3-d ...[more]

PMID: 36139429

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Project description:Liver fibrosis is the excessive expression and accumulation of extracellular matrix proteins in the liver. Fibrotic scarring occurs as the consequence of chronic injury and inflammation. While the successful treatment of hepatitis B and C reduced the burden of liver disease related to viral hepatitis, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) are nowadays the leading causes of hepatic fibrosis worldwide. Although basic research activities have significantly advanced our understanding of the molecular disease pathogenesis, the present therapeutic options for fibrosis are still limited. In advanced disease stages, liver transplantation often remains the only curative treatment. This highlights the necessity of preventive strategies to avoid complications of fibrosis, particularly cirrhosis, portal hypertension and liver cancer. Lifestyle modifications (weight loss, exercise, healthy diet) are the basis for prevention and treatment of NAFLD-associated fibrosis. In the present review, we discuss recent advances in antifibrotic prevention and therapy. In particular, we review the current concepts for antifibrotic drug candidates in the treatment of NAFLD and NASH. While some compounds aim at reverting pathogenic liver metabolism, an alternative approach is to disconnect the injury (e.g., NAFLD) from inflammation and/or fibrosis. Investigational drugs typically target metabolic pathways, insulin resistance, hepatocyte death, inflammatory cell recruitment or activation, the gut-liver axis, matrix expression or matrix turnover. While several promising drug candidates failed in phase 2 or 3 clinical trials (including elafibranor, emricasan and selonsertib), promising results with the farnesoid X receptor agonist obeticholic acid, the pan-PPAR agonist lanifibranor and the chemokine receptor CCR2/CCR5 inhibitor cenicriviroc support the expectation of an effective pharmacological therapy for liver fibrosis in the near future. Tackling NAFLD-associated fibrosis from different directions by combinatorial drug treatment and effective lifestyle changes hold the greatest prospects.

Project description:Hepatocellular carcinoma (HCC) is the most frequently found primary malignancy of the liver, showing an accelerated upward trend over the past few years and exhibiting an increasing relationship with metabolic syndrome, obesity, dyslipidemia and type 2 diabetes mellitus. The connection between these risk factors and the occurrence of HCC is represented by the occurrence of non-alcoholic fatty liver disease (NAFLD) which later, based on genetic predisposition and various triggers (including the presence of chronic inflammation and changes in the intestinal microbiome), may evolve into HCC. HCC in many cases is diagnosed at an advanced stage and can be an incidental finding. We present such a scenario in the case of a 41-year-old male patient who had mild obesity and mixed dyslipidemia, no family or personal records of digestive pathologies and who recently developed a history of progressive fatigue, dyspepsia and mild upper abdominal discomfort initially thought to be linked to post-COVID syndrome, as the patient had COVID-19 pneumonia a month prior. The abdominal ultrasound revealed a mild hepatomegaly with bright liver aspect of the right lobe (diffuse steatosis), a large zone of focal steatosis (segments IV, III and II) and a left lobe tumoral mass, highly suggestive of malignancy. Point shear wave elastography at the right lobe ruled out an end-stage chronic liver disease. Additional laboratory investigations, imaging studies (magnetic resonance imaging) and histopathological examination of liver fragments confirmed a highly aggressive HCC, with poorly differentiation-G3, (T4, N 1M 0) and stage IVA, associated with nonalcoholic steatohepatitis (NASH). A sorafenib course of treatment was attempted, but the patient discontinued it due to severe side effects. The subsequent evolution was extremely unfavorable, with rapid degradation, a few episodes of upper digestive bleeding, hepatic insufficiency and mortality in a couple of months. Conclusions: Diagnosis of NASH-related HCC is either an accidental finding or is diagnosed at an advanced stage. In order to earn time for a proper treatment, it becomes important to diagnose it at an early stage, for which regular check-ups should be performed in groups having the risk factors related to it. Patients suffering from obesity and mixed dyslipidemia should undergo periodic abdominal ultrasound examinations. This should be emphasized even more in the cases showing NASH. Complaints of any kind post-COVID-19 should be dealt with keenly as little is yet known about its virulence and its long-term side effects.

Dataset Information

Human Allogeneic Liver-Derived Progenitor Cells Significantly Improve NAFLD Activity Score and Fibrosis in Late-Stage NASH Animal Model.

Publications

Human Allogeneic Liver-Derived Progenitor Cells Significantly Improve NAFLD Activity Score and Fibrosis in Late-Stage NASH Animal Model.

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