142 Chapter 6 been realized for 2D tissues with simpler microstructures (skin, small intestinal submucosa, and pericardium) [140], organs with higher complexity such as lungs have proven to be more challenging. There are several methods that can be used in combination to decellularize tissues and organs including physical, chemical, or enzymatic as depicted in Figure 3A [141]. Decellularization of lung tissue is mainly achieved by perfusion of decellularization solutions through the airways or vasculature of the lungs or by immersion of tissue segments in these solutions with or without agitation [142]. To mimic the lung microenvironment and stimulate functional organ regeneration, decellularized tissues have been frequently repopulated with a variety of progenitor and stromal cells [142]. Precision cut lung slices (PCLS) have become popular ex vivo experimental models and these can also be used in the decellularized form. A positive feedback loop between IPF ECM and fibroblasts was demonstrated when the diseased ECM stimulated pathological gene expression enriched for ECM proteins in fibroblasts seeded on decellularized IPF PCLS [59]. Recently, ECM deposition by non-diseased lung fibroblasts seeded in acellular non-diseased lung PCLS resembled native lung tissue sections more closely compared to a monolayer of fibroblasts grown on plastic [143]. The influence of the microenvironment on cellular behavior was further demonstrated when non-diseased lung fibroblasts differentially expressed basement membrane proteins when seeded in IPF PCLS compared to non-diseased PCLS [144]. Decellularized lung models have played an indispensable role in unravelling underlying disease mechanisms that promote and enhance pathogenesis. For instance, placental microvascular pericytes sustained phenotypic transition (increased expression of α-SMA) when cultured on decellularized IPF lungs compared to decellularized nondiseased lungs, which facilitated a better understanding of the influence of pericytes in progression of IPF [145]. The crucial role of lysyl oxidase enzymes in increased tissue stiffness was uncovered when its inhibitor, β-Aminoproprionitrile, decreased TGF-β induced thickening of collagen fibers in non-disease decellularized lung scaffolds seeded with non-diseased lung fibroblasts [55].
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