Biomaterials and engineered microenvironments to control YAP/TAZ-dependent cell behaviour - PubMed (original) (raw)

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Biomaterials and engineered microenvironments to control YAP/TAZ-dependent cell behaviour

Giovanna Brusatin et al. Nat Mater. 2018 Dec.

Abstract

Mechanical signals are increasingly recognized as overarching regulators of cell behaviour, controlling stemness, organoid biology, tissue development and regeneration. Moreover, aberrant mechanotransduction is a driver of disease, including cancer, fibrosis and cardiovascular defects. A central question remains how cells compute a host of biomechanical signals into meaningful biological behaviours. Biomaterials and microfabrication technologies are essential to address this issue. Here we review a large body of evidence that connects diverse biomaterial-based systems to the functions of YAP/TAZ, two highly related mechanosensitive transcriptional regulators. YAP/TAZ orchestrate the response to a suite of engineered microenviroments, emerging as a universal control system for cells in two and three dimensions, in static or dynamic fashions, over a range of elastic and viscoelastic stimuli, from solid to fluid states. This approach may guide the rational design of technological and material-based platforms with dramatically improved functionalities and inform the generation of new biomaterials for regenerative medicine applications.

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Conflict of interest statement

Competing interests statement

The authors declare no competing interests.

Figures

Figure 1

Figure 1. Microfabrication and biomaterial designs, their biological effects and YAP/TAZ regulation.

Top panel: Schematic representation of engineered substrates adopted to study the effect of physical and mechanical manipulations on cells. Different stimuli and experimental conditions converge on YAP/TAZ regulation (Activation in Red, Attenuation in Blue). Central oval: the basics of YAP/TAZ mechanotransduction, as their nuclear localization and activity rely on the mechanic coupling of the cell to the ECM through integrin and associated changes in F-actin organization (FA, Focal Adhesions). Bottom panel: table summarizing the biological consequences of biomaterial-based regulation of various cell types broadly adopted in the biomaterial community, and the causality of YAP/TAZ activity levels for these responses.

Figure 2

Figure 2. Dynamic preservation of stem cells in organoid outgrowths requires "conforming" properties of biomaterials.

Schematic representation of a single stem cell, seeded in 3D hydrogels, either natural or synthetic. A) low substrate stiffness causes reduced ECM resistance (dotted arrows) leading to poor cellular traction forces (blue arrows), YAP/TAZ inhibition (OFF) and loss of stemness and of proliferative potential. B) "high" ECM rigidities, whose ideal value depends on the specific cell type, sustain YAP/TAZ activation (ON). This is mediated by stronger resistance of the ECM and build-up of sufficient traction forces by actomyosin contractility, in turn leading to maturation of FA, F-actin remodeling and cellular strain. However, in absence of "conforming" properties of the ECM (C), such as on substrates retaining elastic properties and that cannot be pericellularly degraded, cell division leads to progressive cell confinement, increased cell-cell adhesion (similar to 2D contact inhibition) and reduced traction forces. Note that the ECM remains ideally stiff as in (B). This leads to YAP/TAZ turn off, and loss of stemness and proliferative potential. D) YAP/TAZ driven stemness and proliferation are preserved as long as the material can conform to the proliferative outgrowth of the organoids thanks to biomaterials endowed with viscoelastic properties due either to stress relaxation potential and/or degradation by spontaneous hydrolysis or by MMPs. E) A conforming ECM is permissive for self-organization of the ever expanding organoid, as local patterns of high and low ECM viscolasticity are translated in patterns of YAP/TAZ activity: only cells displaying high mechanical stress retain stemness (YAP/TAZ ON) whereas those experiencing lower traction, contact inhibition and/or reduced MMP expression undergo differentiation permitted by YAP/TAZ turn OFF. The bottom part of the figures outlines the various types of ECM and their associated mechanical behavior.

Figure 3

Figure 3. Biomaterials mimicking altered microenvironments in human diseases.

Each arrow indicates a specific human disease or stem cell behavior, the biomaterialbased system used to investigate it and the biological read-outs.

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