Long-ranged Mechanical Cell–matrix and Cell-cell Interactions in 3D Fibrous Gels

Background: Cells exert mechanical forces that deform the extracellular matrix (ECM) and can reach neighboring distant cells. Such matrix deformation result in highly aligned and dense fiber “bands” between cells; the manner in which such bands are formed over time, their mechanical properties and possible effect on cells behavior remains unclear.

Methods: Fibroblast cells were embedded in 3D fibrin-gels. 4D confocal microscopy images were acquired from matrix polymerization through the formation of intercellular bands. Changes in cell morphology, fiber density and alignment were monitored over time. The role of cell contractility and branching of cell protrusions were examined. Traction force microscopy was used to quantify matrix displacements between the interacting cells.

Results: When cells are sufficiently close together, they can form directed bands due to cellular contractility. Band formation involves a gradual increase in the density and alignment of fibers. Cell-induced forces and branching of cell protrusions are essential to band formation. The deformation of the inter-cellular bands is mostly plastic and irreversible, and involves large matrix displacements. Cells often extend protrusions along the band direction, indicating biological regulation.

Conclusion: Pairs of individual cells can interact mechanically over long distances through the fibrous matrix, and form directed matrix bands that effect cellular activity. Also, our system can be extended to other cell types. Such mechanical connections via the matrix may be essential in various biological processes such as wound healing, organogenesis and cancer progression and metastasis.