Novel approaches to liver disease diagnosis and modeling

Abstract

Lack of a prompt and accurate diagnosis remains on top of the list of challenges faced by patients with rare liver diseases. Although rare liver diseases affect a significant percentage of the population as a group, when taken singularly they represent unique diseases and the approaches used for diagnosis of common liver diseases are insufficient. However, the development of new methods for the acquisition of molecular and clinical data (i.e., genomic, proteomics, metabolomics) and computational tools for their analysis and integration, together with advances in modeling diseases using stem cell-based technology [i.e., induced pluripotent stem cells (iPSCs) and tissue organoids] represent a promising and powerful tool to improve the clinical management of these patients. This is the goal of precision medicine, a novel approach of modern medicine that aims at delivering a specific treatment based on disease-specific biological insights and individual profile. This review will discuss the application and advances of these technologies and how they represent a new opportunity in hepatology.

Keywords: Genomic; induced pluripotent stem cells (iPSCs); metabolomic; organoids; proteomic.

Figure 1

Biological scales in the liver and the application of multi-omics technologies. The high throughput technologies discussed in the text generate data important for the characterization of each scale; however, it is the integration of information in networks (green arrows) that reveal the complexity of liver physiology and diseases (purple arrows).

Figure 2

Generation of iPSC and organoids and their application for the study of liver diseases. iPSCs are generated from the reprogramming of adult somatic cells (i.e., peripheral mononuclear cells and skin fibroblasts) of a patient or a healthy donor in pluripotent stem cells. iPSC can be differentiated in liver parenchymal cells (i.e., hepatocytes and cholangiocytes) by recapitulating in culture the steps of liver development. Liver organoids are established from stem cells derived from bile fluid or from liver biopsy or liver explant tissues, embedded in Matrigel and be supplied with specific factors. Liver organoids can also be generated by iPSC-derived liver cells cultured in similar conditions. Multicellular liver organoids were recently generated directly by differentiation of iPSC and from iPSC derived liver organoids (see text for details). These technologies have shown to be useful to study and model liver development and disease mechanisms, to discover new gene functions, to test existing and new drugs and to potentially be applied to regenerative medicine.