169 Current possibilities and future opportunities with three-dimensional lung ECM-derived hydrogels THE POSSIBILITIES WITH LUNG ECM-DERIVED HYDROGELS Lung ECM-derived hydrogels for mimicking in vivo ECM biochemical composition The ECM, including in the lung, is a complex structure of proteins, glycoproteins, matricellular proteins and many other regulatory proteins and enzymes that keep this dynamic structure in balance during tissue homeostasis [40]. Mimicking such a complex structure when generating an in vitro 3D environment in which to culture cells to study cell:matrix interactions is impossible when starting with individual components. Sourcing the ECM from decellularized lungs has provided an opportunity to develop hydrogels that reflect a major proportion of the elements within this complex mixture. The process of decellularization requires treating the tissue with a range of detergents and/or salt solutions [1, 41, 42] that do remove some of the elements that are part of the matrisome, particularly growth factors bound to the ECM and some glycoproteins, but the major structural fibres are retained during this process. Early proteomic studies [1, 43] illustrated the retention of many components of the lung matrisome in decellularised scaffolds from control and diseased lung samples. A recent study from the team in the Weiss lab [44], has elegantly shown that the components of the ECM are specific for different compartments within the lung (airways, alveolus, blood vessels), and that these change during chronic lung disease. These decellularized scaffolds from lung tissues have now been used as a source of ECM for the generation of hydrogels. The processing of the scaffolds to generate the solution that will gel when brought to physiological conditions is not thought to lead to further loss of ECM components, making this an ideal method for developing a 3D in vitro model system in which cells can be cultured in the presence of this complex mixture of the lung ECM microenvironment. It remains to be seen if the absence of the elements of the matrisome that are lost during the decellularisation process impose a limitation in the interpretation of data generated when cells are seeded in such hydrogels (Figure 1). The absence of growth factors anchored in the ECM scaffolds, and therefore the ECM-derived hydrogels, after the decellularization process may be considered a limitation, although it is evident that the growth factor retentive properties of the ECM are retained as growth factors supplied in growth media or as part of the secretome from other cells are rapidly absorbed and then subsequently released from the ECM hydrogels [45]. In addition, ECM-derived hydrogels are a source of extracellular vesicles [46], adding another aspect to the regulatory processes induced by these cell support structures. 7
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