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Models for cell behaviour within tissues

Cells sense and adapt to endogenous and exogenous forces through their adhesion with the extracellular matrix (ECM). Understanding how cells respond in a three-dimensional microenvironment is central to designing therapeutic interventions for fibrous tissue pathologies.
Models for cell behaviour within tissues
Under physiological conditions, tissue homeostasis involves the continuous synthesis of ECM components to maintain cell adhesion. Various fibrous tissue pathologies are characterised by adverse tissue remodelling and matrix disorganisation. Accumulating evidence implicates matrix adhesion proteins, which fail to respond under mechanical stimulation and lead to fibrous tissue pathology.

The scope of the EU-funded MACS (The contribution of cellular adhesions to matrix remodeling in health and disease) project was to address how mechanosensitive matrix adhesion-associated proteins react to mechanical perturbations and impact matrix remodelling. In this context, researchers engineered micro-tissues from novel 3D tissue platforms and subjected them to mechanical stimuli.

Project results showed that fibroblasts had a high ECM remodelling capacity when in contact with fibronectin alone and a reduced repair ability in the presence of collagen 1. In a 3D tissue platform, experiments showed that only full-length fibronectin promoted fibroblast migration and force generation. In addition, gradients of fibronectin conformation and ECM composition within the tissue contributed to tissue morphogenesis and cell migration.

Upon cyclic stretch, microtissues containing fibroblasts with collagen 1 resulted in a transient change in the orientation of actin stress fibres. Quantification of critical matrix adhesion proteins at various time-points indicated changes in expression upon stretch. In another part of the project, scientists demonstrated the importance of the structural organisation of the matrix in cell behaviour. A pathologically organised matrix appears to directly influence the cells to contribute to disease progression rather than its resolution.

Collectively, the findings of the MACS study provided important knowledge on the role of matrix composition and organisation in cell behaviour and tissue homeostasis. Considering the medical challenge posed by fibrous tissue pathologies, reversing pathological ECM compositional changes early on appears to be a promising intervention.

Related information

Keywords

Tissue, extracellular matrix, microenvironment, fibrous tissue pathology, fibroblast, fibronectin
Record Number: 190629 / Last updated on: 2016-11-29
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