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Directed fibroblast migration is central to highly proliferative processes inregenerative medicine and developmental biology, such as wound healing andembryogenesis. However, the mechanisms by which single fibroblasts affect eachother's directional decisions, while chemotaxing in microscopic tissue pores,are not well understood. Therefore, we explored the effects of two types ofrelevant social interactions on fibroblast PDGF-BB-induced migration inmicrofluidic tissue-mimicking mazes: cell sequence and mitosis. Surprisingly,it was found that in both cases, the cells display behavior that iscontradictory to the chemoattractant gradient established in the maze. In caseof the sequence, the cells do not like to take the same path through the mazeas their predecessor, when faced with a bifurcation. To the contrary, they tendto alternate - if a leading cell takes the shorter (steeper gradient) path, thecell following it chooses the longer (weaker gradient) path, and vice versa.Additionally, we found that when a mother cell divides, its two daughters go inopposite directions (even if it means migrating against the chemoattractantgradient and overcoming on-going cell traffic). Therefore, it is apparent thatfibroblasts modify each other's directional decisions in a manner that iscounter-intuitive to what is expected from classical chemotaxis theory.Consequently, accounting for these effects could lead to a better understandingof tissue generation in vivo, and result in more advanced engineered tissueproducts in vitro.

Cell Sequence and Mitosis Affect Fibroblast Directional Decision-Making during Chemotaxis in Tissue-Mimicking Microfluidic Mazes