Researchers identify how cells get their orders to heal wounds

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Leader cells, shown here in fluorescent green, rush to the site of a wound with the follower cells in their wake (Photo: Pak Wong)

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When you cut on your finger or scrape your knee, cells rush to the wound and repair or replace the damaged tissue. But how exactly this works – in particular how certain cells become "leaders" in the process – has long been a mystery. Now researchers at the University of Arizona (UA) have identified the mechanisms that cause and regulate this collective cell migration. Armed with this knowledge, biomedical engineers will be able to design new tissue regeneration treatments for diabetes and heart disease as well as for slowing or stopping the spread of cancer.

Leader cells earn their name for being the genetic messengers that move at the front of a cell group migrating to a wound. The UA researchers found that leader cells get their orders from a protein molecule called DII4, which acts as coordinator for the whole process. Nearby cells get sent to heal the wound, with identical cells specializing into leader and follower cells. The leader cells send signals to the follower cells, which have none of the messenger RNA from the DII4 protein, and this continues until new tissue covers the wound.

This migration process is also used by cancer cells to spread into healthy tissue.

To uncover the secrets behind how they work, the UA researchers tracked leader cell formation and behavior in in vitro human breast cancer cells and mice epithelial cells using a number of different techniques – single-cell gene expression analysis, computational modelling, and time-lapse microscopy. Lead investigator Pak Kin Wong also noted with amazement that when individual leader cells were destroyed with a laser, new ones took their place.

Stephanie Wellington and Zachary Dean, two students in Pak Kin Wong's research group, manipulate cells using a microfluidic device

The research has opened new doors in biomedical engineering. "Knowing the genetic makeup of leader cells and understanding their formation and behavior gives us the ability to alter cell migration," said Pak Kin Wong.

With this ability, cancer cells could be stopped in their tracks. Normal cells could be directed to heal damaged tissue that for whatever reason has been ignored by the body's internal healing processes (such as can happen with diabetes). Plaque buildup in arteries could be reduced. And bioengineered tissues and organs meant for human transplantation could perhaps be developed faster.

A paper describing the research was published in the journal Nature Communications.

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