167 Current possibilities and future opportunities with three-dimensional lung ECM-derived hydrogels INTRODUCTION The human body is a complex, dynamic environment, consisting of many different cell types that reside in or traverse through defined microenvironments, which is tightly regulated to maintain a healthy state. When elements within this system become disrupted, this can lead to the development of disease. In the lung, disruption of the complex interplay between cells and the extracellular matrix (ECM), the scaffold that provides support and biochemical and biomechanical cues, is emerging as a key element for deciphering the mechanism underlying diseases. WHY SHOULD WE THINK ABOUT 3D IN IN VITRO MODEL SYSTEMS? When we think about the lung in vivo, we readily acknowledge that it is a flexible, relatively soft tissue that is three dimensional (3D) in structure. However, in general, when we work with model systems in vitro, to try to elucidate processes that underlie homeostasis and disease, we mostly work with two dimensional (2D) systems. In the lung cells are surrounded by a specialised ECM, that is appropriate for their location. Mesenchymal cells are located within a 3D ECM structure, while epithelial and endothelial cells are usually attached to a basement membrane on their basal side and their apical side is subjected to flow of epithelial lining fluid or blood respectively. The stiffness of the lung tissue, in health is usually between 1-5 kilo-pascals (kPa), and in fibrotic disease this can increase up to 100 kPa although the pattern of stiffness can be very heterogeneous [1, 2]. 2D systems are frequently based on a tissue culture plastic or glass surface, with a stiffness in the gigapascal range, and all cells are grown with polarity. While a lot has been gained from working in 2D systems there is now an opportunity to move forward with our models to establish cells in an environment that reflects the physiological conditions in the lung. The literature builds a strong body of evidence that the microenvironment in which a cell resides dictates its responses. From simple single ECM component studies [312], through to more complex cell deposited ECM studies [13-15], the influence of the ECM components on lung cell proliferation, migration, factor output and response to treatment is evident. However, this information has been collated from cells exposed to ECM components in 2D. It is recognised that cells in a 3D environment have differential responses compared to those in 2D [16, 17]. Therefore, developing systems where the influence of the ECM and the microenvironment in 3D can be explored will represent a next step forward for understanding disease underlying mechanisms in the lung. 7
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