Three dimensional fibrotic extracellular matrix directs microenvironment fiber remodeling by fibroblasts

Idiopathic pulmonary fibrosis (IPF), for which effective treatments are limited, results in excessive and disorganized deposition of an aberrant extracellular matrix (ECM). An altered ECM microenvironment is postulated to contribute to disease perpetuation in a feed-forward manner through inducing profibrotic behavior by lung fibroblasts, the main producers and regulators of ECM. Here, we examined this hypothesis in a 3D in vitro model system by growing primary human lung fibroblasts in ECM-derived hydrogels from non-fibrotic (control) or IPF lung tissue. Culture of fibroblasts in fibrotic hydrogels did not trigger a change in the overall amount of collagen or glycosaminoglycans but did cause a drastic change in fiber organization compared to culture in control hydrogels. Mechanical properties of fibrotic hydrogels were modified by fibroblasts while control hydrogels were not. These results illustrate how the 3D microenvironment plays a crucial role in directing cells to exhibit pro-fibrotic responses by providing biochemical and/or biomechanical cues. ### Competing Interest Statement MN, TK, BNM, IHH and JKB receive unrestricted research funds from Boehringer Ingelheim. MJT, CKW, ESW and KCK are employees of Boehringer Ingelheim. All other authors have no competing interests.