![]() ![]() For example, synthetic hydrogel-based cell culture substrates with tunable stiffness have helped establish a paradigm for mechanosensing during MF differentiation in two-dimensions (2D), where compliant matrices maintain fibroblast quiescence in contrast to stiffer matrices that promote MF differentiation ( 10, 11). Synthetic hydrogels that are more resistant to cell-mediated degradation have provided a better controlled setting for long-term studies of disease-related processes ( 9). Rapid degradation kinetics (1 to 3 days) and resulting issues with material stability (1 to 2 weeks) further impede the use of natural materials for studying fibrogenic events and drug responses, which occur over weeks to months in in vivo models or years in patients ( 7, 8). However, their utility in identifying physical microenvironmental determinants of MF differentiation suffers from an intrinsic coupling of multiple biochemical and mechanical material properties ( 6). Seminal studies using natural type I collagen gels have elucidated the role of profibrotic soluble cues in promoting cell contractility, ECM compaction, and MF differentiation, and more recently, precision-cut lung slices, have emerged as a powerful tool to study the complexity of the pulmonary microenvironment in IPF ( 4, 5). ![]() Consequently, natural and synthetic in vitro tissue models have provided great utility for the study of MF mechanobiology. However, a precise understanding of how physical cues from the microenvironment influence MF differentiation in vivo is confounded by concurrent structural (e.g., collagen density and laminin/elastin degradation) and biochemical (e.g., matrix composition and inflammatory) changes to the microenvironment ( 4). Preclinical models of fibrosis in mice have supported the link between tissue stiffening and disease progression. Undoubtedly, the limited efficacy of antifibrotic drugs at present underscores limitations of existing models for identifying therapeutics, the complexity of the disease, and an incomplete understanding of MF biology.Ī strong correlation between lung tissue stiffening and worse patient outcomes suggests an important role for matrix mechanosensing in fibrotic disease progression ( 3). As organ transplantation remains the only curative option for late-stage disease, effective antifibrotic therapeutics that slow MF expansion or even reverse fibrosed tissue remain a major unmet clinical need. MFs drive eventual organ failure through excessive fibrous ECM deposition, force generation and tissue contraction, and eventual disruption of parenchymal tissue function ( 1). These critical cellular mediators of fibrogenesis are primarily derived from tissue-resident fibroblasts ( 1). Often described as dysregulated or incessant wound healing, fibrosis involves persistent cycles of tissue injury and deposition of extracellular matrix (ECM) by myofibroblasts (MFs). In particular, interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF), are fatal and incurable with a median survival of only 2 to 5 years ( 2). Given our observation that compliant degradable 3D matrices amply support fibrogenesis, these studies demonstrate a departure from the established relationship between stiffness and myofibroblast differentiation in 2D, and provide a new 3D model for studying fibrosis and identifying antifibrotic therapeutics.įibrosis is implicated in nearly 45% of all deaths in the developed world and plays a role in numerous pathologies, including pulmonary fibrosis, cardiac disease, atherosclerosis, and cancer ( 1). ![]() Using a multistep bioinformatics analysis of IPF patient transcriptomes and in vitro pharmacologic screening, we identify matrix metalloproteinase activity to be essential for 3D but not 2D myofibroblast differentiation. In contrast to findings on 2D hydrogels, myofibroblast differentiation in 3D was inversely correlated with hydrogel stiffness but positively correlated with matrix fibers. Here, we describe a multicomponent hydrogel that recapitulates the 3D fibrous structure of interstitial tissue regions where idiopathic pulmonary fibrosis (IPF) initiates. Although the extracellular matrix becomes increasingly stiff and fibrous during disease progression, how these physical cues affect myofibroblast differentiation in 3D is poorly understood. Fibrosis, characterized by aberrant tissue scarring from activated myofibroblasts, is often untreatable. ![]()
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