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

TL;DR

This study reveals that fibroblast cells in tissue-like microfluidic environments make counter-intuitive migration decisions influenced by cell sequence and division, challenging classical chemotaxis expectations and impacting tissue engineering.

Contribution

It uncovers how fibroblast interactions during chemotaxis involve alternating paths and opposite directions post-mitosis, providing new insights into cell decision-making mechanisms.

Findings

Cells tend to alternate paths at bifurcations, avoiding the same route as predecessors.

Mother cell division results in daughter cells migrating in opposite directions.

Fibroblast behavior contradicts classical chemotaxis gradient expectations.

Abstract

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