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Mechanical forces regulate the interactions of fibronectin and collagen I in extracellular matrix.

ABSTRACT: Despite the crucial role of extracellular matrix (ECM) in directing cell fate in healthy and diseased tissues--particularly in development, wound healing, tissue regeneration and cancer--the mechanisms that direct the assembly and regulate hierarchical architectures of ECM are poorly understood. Collagen I matrix assembly in vivo requires active fibronectin (Fn) fibrillogenesis by cells. Here we exploit Fn-FRET probes as mechanical strain sensors and demonstrate that collagen I fibres preferentially co-localize with more-relaxed Fn fibrils in the ECM of fibroblasts in cell culture. Fibre stretch-assay studies reveal that collagen I's Fn-binding domain is responsible for the mechano-regulated interaction. Furthermore, we show that Fn-collagen interactions are reciprocal: relaxed Fn fibrils act as multivalent templates for collagen assembly, but once assembled, collagen fibres shield Fn fibres from being stretched by cellular traction forces. Thus, in addition to the well-recognized, force-regulated, cell-matrix interactions, forces also tune the interactions between different structural ECM components.

SUBMITTER: Kubow KE

PROVIDER: S-EPMC4539566 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Mechanical forces regulate the interactions of fibronectin and collagen I in extracellular matrix.

Kubow Kristopher E KE Vukmirovic Radmila R Zhe Lin L Klotzsch Enrico E Smith Michael L ML Gourdon Delphine D Luna Sheila S Vogel Viola V

Nature communications 20150814

Despite the crucial role of extracellular matrix (ECM) in directing cell fate in healthy and diseased tissues--particularly in development, wound healing, tissue regeneration and cancer--the mechanisms that direct the assembly and regulate hierarchical architectures of ECM are poorly understood. Collagen I matrix assembly in vivo requires active fibronectin (Fn) fibrillogenesis by cells. Here we exploit Fn-FRET probes as mechanical strain sensors and demonstrate that collagen I fibres preferenti ...[more]

PMID: 26272817

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Project description:The invasive and metastatic spread of ovarian cancer (OC) results from the cooperative interactions between cancer and stroma, which include acellular extracellular matrix (ECM) and cellular components, such as cancer-associated fibroblasts (CAFs). Soluble growth factors secreted by cancer and stromal cells contribute to stroma remodeling through the synthesis and modification of ECM proteins, providing a favorable environment for cancer cell dissemination. Within the OC, the peptide endothelin-1 (ET-1), through two G protein-coupled receptors, ET A R and ET B R, supports tumor growth and progression by acting on both cancer and stromal cells. Many of these effects rely on the functional and molecular link with the protein b-arrestin1 (b-arr1). However, the precise role of ET-1 in regulating the expression of ECM proteins by primary human ovarian fibroblasts (HOFs) remains unclear. In this study, we aimed to elucidate the regulatory role of ET-1 in the expression of type I collagen (Col1) and fibronectin 1 (FN1). We report a significant increase in the expression of both Col1 and FN1 in cells stimulated with ET-1, both at mRNA and protein levels, reaching the amounts of proteins found in ovarian CAFs. The observed effects are associated with the activation of both receptors since they are impaired by treatment with either ET A R or ET B R antagonists in HOFs and CAFs. Furthermore, they are particularly affected by the dual ET A R/ET B R antagonist bosentan, in vitro and in vivo models. At the molecular level, ET-1 activates the Col1 promoter and enhances the expression of this gene through the nuclear function of β-arr1. The change in transcriptome of HOFs silenced for β-arr1 was analyzed to confirm the molecular response triggered by β-arr1, which resulted in the upregulation of ECM remodeling and collagen deposition. In summary, these findings demonstrate that the ET-1 axis may contribute to the remodeling of the ECM and probably to the early stages of OC progression by modulating the expression of Col1 and FN1. The targeting of ET-1 signaling with ET A R/ET B R antagonists may impede HOFs’ ability to produce key ECM proteins in this tumor.

Dataset Information

Mechanical forces regulate the interactions of fibronectin and collagen I in extracellular matrix.

Publications

Mechanical forces regulate the interactions of fibronectin and collagen I in extracellular matrix.

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