The extracellular matrix (ECM) provides important structural support for cells in multicellular tissues and it also plays a role in guiding migration. For example, aligned matrix fibers can provide routes for directed movement. Cells can interact with their surrounding ECM biochemically as well as physically, but can cells steer the direction of these fiber tracks and how does this happen in real time? We studied the dynamics and mechanisms of matrix alignment around engineered three-dimensional (3D) multicellular tissues prior to migration and found that tissue-derived forces in the form of cytoskeletal tension are primarily responsible for rapidly aligning matrix fibers by applying strain to the ECM in a matter of hours. This process results a pattern of fibers oriented perpendicular to the tissue surface, which can then serve as directed paths for subsequent cell migration outwards from the original tissue geometry. Cells can indeed form tracks in a specific direction prior to migrating!

The cover for the August 8, 2017 issue of Biophysical Journal is an image of a 3D multicellular fibroblast tissue undergoing collective migration captured by Alexandra Piotrowski-Daspit; it was taken while she was a graduate student at Princeton University. The fibroblasts are seen migrating along collagen fibers that were initially aligned radially around the tissue surface via tissue-induced strain. Strikingly, the migration pattern is also radially outwards from the tissue that was originally circular in geometry (~100 mm in diameter). The tissue was imaged at focal planes spanning its entire depth (~50 mm) using confocal fluorescence microscopy with a 40×oil-immersion objective. The actin fibers in the fibroblasts are represented in pink. Collagen fibers in the ECM are shown in green and were visualized using confocal reflectance microscopy. The two channels were merged and the confocal stack was projected onto one two-dimensional (2D) image.

Our study revealed that coordinated cytoskeletal contractility within multicellular tissues drives ECM alignment regardless of cell type, as we noted the same behavior in normal epithelial, breast cancer, and fibroblast cells. Moreover, tissue-induced fiber alignment always precedes migration. The ability of cells to rapidly align their matrix prior to migration is likely to aid in quick reactions to changing microenvironmental cues. Further, we confirm the importance of biomechanics in the physical interplay between cells and their surrounding matrix. Our results have wide-ranging implications, as cell migration is a key biological process used during normal tissue development, wound healing, and cancer invasion.

—Alexandra Piotrowski-Daspit, Bryan Nerger, Avi Wolf, Sankaran Sundaresan and Celeste Nelson