Architecture in 3D cell culture: An essential feature for in vitro toxicology

Abstract

Three-dimensional cell culture has the potential to revolutionize toxicology studies by allowing human-based reproduction of essential elements of organs. Beyond the study of toxicants on the most susceptible organs such as liver, kidney, skin, lung, gastrointestinal tract, testis, heart and brain, carcinogenesis research will also greatly benefit from 3D cell culture models representing any normal tissue. No tissue function can be suitably reproduced without the appropriate tissue architecture whether mimicking acini, ducts or tubes, sheets of cells or more complex cellular organizations like hepatic cords. In this review, we illustrate the fundamental characteristics of polarity that is an essential architectural feature of organs for which different 3D cell culture models are available for toxicology studies in vitro. The value of tissue polarity for the development of more accurate carcinogenesis studies is also exemplified, and the concept of using extracellular gradients of gaseous or chemical substances produced with microfluidics in 3D cell culture is discussed. Indeed such gradients-on-a-chip might bring unprecedented information to better determine permissible exposure levels. Finally, the impact of tissue architecture, established via cell-matrix interactions, on the cell nucleus is emphasized in light of the importance in toxicology of morphological and epigenetic alterations of this organelle.

Keywords: Basement membrane; Cell nucleus; Microfluidics; Organ-on-a-chip; Polarity; Tight junction.

Figure 1. Examples of polarity axis in various organs or functional units of organs

Simple drawings represent the cells in which polarity is established with, at the apical pole, the presence of tight junctions at lateroapical cell-cell contacts, and at the basal pole, contacts with the ECM (most often a basement membrane type of ECM or a modified version of a basement membrane). Note: Not all cell types in a particular organ are represented.

Figure 2. Applying a chemical gradient in cell culture

A cell culture specimen receives a chemical at increasing concentrations (as displayed by the widening triangle and the arrows) depending on the location in the culture area. Here cells of an epithelium are represented by rectangles with nuclei drawn in black, in the culture platform. With such system, it is possible to create controlled heterogeneity of the presence of the chemical throughout the culture surface. It is also possible to identify concentration thresholds for the impact of the chemical on cells depending on a given variation in cell culture parameters.