Advanced preclinical models for evaluation of drug-induced liver injury – consensus statement by the European Drug-Induced Liver Injury Network [PRO-EURO-DILI-NET]

Abstract

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

New Perspectives to Improve Mesenchymal Stem Cell Therapies for Drug-Induced Liver Injury

“…The lack of precise experimental models that recapitulate the physiopathology of human DILI is one of the key points related to the lack of correlation between the preclinical data and the results observed in clinical trials and requires a separate section. To date, not a single model that accurately reproduces all aspects of human liver injury, including DILI, has been established [ 128 , 129 ].…”

“…The in vitro approaches to study the therapeutic effects of MSCs on DILI can be controlled more closely than in vivo approaches. However, the selected conditions may not reflect those present in vivo well enough, like specific cell-to-cell interactions, the marked heterogeneity of enzyme activity of hepatocytes along the porto-central axis and the direct or indirect impact of drugs on other hepatic cells such as endothelial, Kupffer, stellate or biliary epithelial cells [ 128 ].…”

“…Significant progress has been made in the creation and use of humanized mice, although some methodological limitations still need to be resolved, including complications in the reproduction of standard chimeras, residual host immunoreactivity and a limited number of human cell types that can be used for xenotransplantation [ 128 ].…”

3D Hepatic Organoid-Based Advancements in LIVER Tissue Engineering

“…Therefore, effective models for evaluating disease mechanisms to sketch therapeutic approaches and screen potential drugs for liver diseases are an area of prime interest. Over the years in vivo animal models have played a crucial role in understanding liver pathophysiology and preclinical evaluation of drug effectivity [ 2 ]. However, challenges in replication of organ-level physical and chemical microenvironment in two-dimensional in vitro cultures and genotypically different, ethically constraint in vivo rodent models, warrants a need to fabricate in vivo mimicking three-dimensional (3D) in vitro models while addressing healthcare solutions in the current time.…”

C-Reactive Protein, a Promising Approach for Acetaminophen Hepatotoxicity

“…However, despite intensive efforts, the mechanisms involved in APAP hepatotoxicity are not fully understood, which has hampered the availability of effective therapy for APAP hepatotoxicity. 1 , 2 N -acetylcysteine (NAC) is the standard treatment for APAP hepatotoxicity and other causes of ALF. 3 However, the effectiveness of NAC in APAP hepatotoxicity is limited to early administration, indicating the need to identify new strategies for adequate management of ALF caused by APAP hepatotoxicity.…”