219 Fibroblast remodeling of extracellular matrix is directed by the fibrotic nature of the threedimensional microenvironment INTRODUCTION Tissue fibrosis results from an increase in fibroblasts with an aberrant deposition of extracellular matrix (ECM) and abnormal alterations of the ECM structure and composition [1]. While fibrosis is recognized as a coinciding phenomenon in some diseases, such as in inflammatory diseases or several cancers, organ fibrosis itself is one of the leading causes of death worldwide each year [2]. Among these diseases, idiopathic pulmonary fibrosis (IPF) has a worse prognosis than most cancers and remains incurable to date [3]. Currently, IPF is thought to originate from repeating (micro)injuries to the lung epithelium resulting in an aberrant tissue repair response [4]. During this aberrant tissue repair response, fibroblasts emerge as key players that deposit ECM in an abnormal manner, resulting in scarring of lung interstitium that impairs gas exchange in lungs of patients with IPF [5]. Although there is an urgent unmet need for developing novel treatment strategies, lack of appropriate animal models that recapitulate this human disease hinders this process [6]. For new and improved therapeutics against IPF, our understanding of how fibrotic responses are perpetuated and how IPF progresses needs to be advanced. ECM is drastically altered in fibrotic lung diseases both biochemically and biomechanically [7]. While collagen deposition in the alveolar septa is considered one of the hallmarks of fibrotic scar development, numerous other ECM components such as fibronectin, hyaluronic acid, periostin and fibulin-1 are also present to a greater extent in fibrotic lung ECM [8]. In addition to altered ECM composition, fiber structure in fibrotic ECM is also substantially different compared to healthy ECM: fibrotic lungs having a higher percentage of disorganized collagen [9, 10]. Such changes in the fiber organization and content are also postulated to translate into the well-documented changes in the mechanical properties of fibrotic tissue: IPF lungs are many-fold stiffer than control counterparts [11]. Recently, decreased stress relaxation properties of fibrotic lungs were also described, illustrating not only stiffness but also additional mechanical parameters accompany lung fibrosis [12]. Although initially thought of as an inert structure that only provided a physical scaffold, ECM has now been shown to instruct behavior of resident and transmigratory cells [13]. ECM deposited by fibroblasts in fibrosis resulted in activation of naïve fibroblasts seeded onto this ECM [14]. In addition to the origin of the microenvironment, the dimensionality of the environment (two-dimensional (2D) vs. three-dimensional (3D)) has been shown to influence how fibroblasts respond to their microenvironment [15]. While these pioneering studies illustrate that a fibrotic microenvironment instructs cellular behavior, the influence of a 3D fibrotic microenvironment on fibroblasts remains unexplored. 9
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