Abstract
Liver cell types derived from induced pluripotent stem cells (iPSCs) share the potential to investigate development, toxicity, as well as genetic and infectious disease in ways currently limited by the availability of primary tissue. With the added advantage of patient specificity, which can play a role in all of these areas. Many iPSC differentiation protocols focus on 3 dimensional (3D) or organotypic differentiation, as these offer the advantage of more closely mimicking in vivo systems including; the formation of tissue like architecture and interactions/crosstalk between different cell types. Ultimately such models have the potential to be used clinically and either with or more aptly, in place of animal models. Along with the development of organotypic and micro-tissue models, there will be a need to co-develop imaging technologies to enable their visualization. A variety of liver models termed “organoids” have been reported in the literature ranging from simple spheres or cysts of a single cell type, usually hepatocytes, to those containing multiple cell types combined during the differentiation process such as hepatic stellate cells, endothelial cells, and mesenchymal cells, often leading to an improved hepatic phenotype. These allow specific functions or readouts to be examined such as drug metabolism, protein secretion or an improved phenotype, but because of their relative simplicity they lack the flexibility and general applicability of ex vivo tissue culture. In the liver field these are more often constructed rather than developed together organotypically as seen in other organoid models such as brain, kidney, lung and intestine. Having access to organotypic liver like surrogates containing multiple cell types with in vivo like interactions/architecture, would provide vastly improved models for disease, toxicity and drug development, combining disciplines such as microfluidic chip technology with organoids and ultimately paving the way to new therapies.
Highlights
Organoids are in vitro cellular systems that self-organize through mechanisms similar to in vivo, they recapitulate the structure and in many cases the function of the in vivo tissue in question, providing utility in both the clinical and basic research arenas [1, 2]
Whilst many 3 dimensional (3D) liver models are described as organoids these are clearly not all organotypic, a point previous reviews have not addressed
The different types of models explored above reveal that more physiological approaches are important to accurately recapitulate the complexities of disease/development, which involve multiple cell types and their coordination into physiologically relevant structures
Summary
Organoids are in vitro cellular systems that self-organize through mechanisms similar to in vivo, they recapitulate the structure and in many cases the function of the in vivo tissue in question, providing utility in both the clinical and basic research arenas [1, 2]. Treatment of these spheroids with fibrogenic and hepatotoxic compounds resulted in signs of fibrosis such as iHSC activation, extracellular matrix (ECM) secretion and deposition, highlighting the interaction between the two cell types within the organoids and illustrating their use as a disease and toxicity model These cultures could potentially be used to investigate mechanism and treatment, as well as investigating the interplay between hepatocytes and HSCs. The inclusion of two liver cell types demonstrates the advantages of increased complexity in the model over a single cell system. This MSC driven bud formation acts as a “proof of concept” and was proposed as a Frontiers in Medicine | www.frontiersin.org
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