129 3D lung models – 3D extracellular matrix models INTRODUCTION The non-cellular component in all tissues and organs is the extracellular matrix (ECM). The ECM fulfils an essential role acting as a physical scaffolding, while initiating critical biochemical and biomechanical cues for all cells that reside within it [1]. The ECM mainly consists of fiber-forming and interfibrillar molecules. Collagen and elastin are categorized as fiber-forming molecules, whereas proteoglycans and glycoproteins are considered interfibrillary molecules [2]. Healthy ECM is crucial for cells, as it modulates events such as migration and adhesion [3]. All tissues and organs have their own specific ECM, adapted to meet the individual needs to ensure that the organ can fulfil its defined roles. Within the lung, the ECM consists of two main compartments; the basal membrane, which is a specialized layer under the epithelial and endothelial cells, and the interstitial matrix [4]. Fibroblasts are recognized as the cell type responsible for the maintenance and majority of the ECM production [5]. During lung development, the ECM not only provides the developing organ structure but it is also important for the regulation of cell functions such as proliferation, migration and differentiation [6]. Fibroblasts are crucial during development and homeostasis, in their role as the gatekeepers responsible for production, deposition and maintenance of the ECM, residing throughout the organ [7, 8]. Dynamic changes within the ECM are associated with several chronic lung diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), illustrating the essential role of the ECM in the lung at all stages of life [9]. In addition to its role as a scaffold, the ECM has also been recognized as a key regulator of a myriad of biological processes including cell migration, growth, survival, differentiation and metabolism [8, 10]. The lung ECM consists of a multitude of macromolecules of which the major constituents include elastin, collagens, glycosaminoglycans (GAGs), proteoglycans (PGs) and glycoproteins (Figure 1). These macromolecules specifically fulfill roles contributing to the maintenance of the ECM biomechanical characteristics and function of the lung. Elastin is one of the principal constituents of lung ECM and represents 20-30, 7-16 and 3-5% dry weight of parenchyma, blood vessels and airways, respectively [11]; providing the lung its extension and recoil properties [12]. One of the most abundant ECM proteins in the lung is collagen, which comprises 28 different types categorized according to their structure and function as fibrils, fibril-associated collagens with interrupted triple helices, network-forming, beaded filaments and anchoring fibrils collagens [10, 13]. GAGs are polysaccharides with highly hydrophilic proprieties which contribute to the viscoelasticity of the lung [14]. Additionally, GAGs are known as regulators of immune responses, growth 6
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