Self-organization of tissue-equivalents: The nature and role of contact guidance

The morphology and behaviour of tissue cells when surrounded by a network of protein fibres, such as for a tissue-equivalent comprising cells entrapped in a type I collagen gel, is distinct from that when cells are cultured on a rigid surface, and physiologically relevant. The highly elongated and apparently bipolar morphology leads to a 'reversing' type of cell movement in gels, as opposed to a directionally persistent movement characteristic of highly spread, polar cells on surfaces. However, the hallmark of a tissue-equivalent is consolidation of the fibrillar network, or gel compaction, resulting from traction exerted by the cells. When the gel is mechanically constrained from compacting, alignment of the fibrils occurs, inducing cell alignment through a contact guidance response. In order to understand this 'self-organization' of tissue-equivalents, some relevant structural and mechanical properties of collagen gel are considered first, followed by a review of seminal studies of cell traction and tissue-equivalent compaction. Random cell migration in an isotropic gel is then discussed, including a modification of the persistent random walk model used to analyse cell migration on surfaces, followed by a review of contact guidance studies in gels with fibrils having defined alignment. With this background, observations of self-organization of mechanically constrained compacting tissue-equivalents are summarized and explained using a mechanical theory that relates traction-induced compaction to fibre alignment and consequent contact guidance, i.e. a strain-based rather than stress-based cell response to gel compaction. Data in support of this theory obtained from studies involving the controlled applied compression of tissue-equivalents are then presented. Finally, possible mechanisms of contact guidance are discussed.