Healing wounds without scars

Quickly healing a wound is a key part of our skin’s defence against bacteria and other microbes that could cause infection. The price we pay for that speed, though, is often a scar. But can we make skin regenerate without scarring, or even reproduce complex mini-organs like hair follicles that are also often lost to injury? It must be possible, because developing foetuses can do it, and as Eva Higginbotham heard from Washington State University’s Ryan Driskell, he thinks he’s found a gene that might be the key to the process...

Ryan - So there's a lot of research that was done by Michael Longacre and his mentor, and they were doing these life saving in utero surgeries. And what he found was when those babies were born, they didn't have a scar, even though he had done surgery in utero on those fetuses. And that was a remarkable discovery. So one of the things we wanted to do is identify not only a molecular factor, but also the cell types that are lost during skin maturation that would convey this ability of embryonic or neonatal skin to be able to regenerate. And the first step that we did was we started to do single cell RNA sequencing. So single cell RNA sequencing is a new technique that's been developed so that you can sequence, as much as possible, all of the genes that are expressed within a cell. And then from there, you can sequence thousands of cells within a tissue to identify cell populations. And using that technique on say, comparing all of the genes within a cell of over 5 to 10,000 cells in young skin, and then comparing that same assay in old skin, you could find new cell types as well as the genes that are defining those cell types. And that's what we did.

Eva - I see. So you found new cell types that were involved in really effective scarless wound healing and young skin.

Ryan - I would say we rediscovered them and we verified that they were there and that those cell types, in that cellular state, disappear in older skin. And we defined that cellular state by at least one gene - there are other genes that we found as well, but the gene that we decided to choose was LEF-1 and they're there in the young skin and they're not there once the skin matures.

Eva - So what is LEF-1 doing?

Ryan - Right. So LEF-1 is a transcription factor. A transcription factor is a protein that binds to DNA, and many transcription factors bind to DNA to control the regulation of genes to be expressed or sometimes to be inhibited. LEF-1 has been identified to be able to modulate signals from the outside of the cell called Wnts that come from other cell types or through its own signaling. And it's a part of a signaling pathway that's important during development and for some reason is somewhat turned off as the skin ages.

Eva - So once you found LEF-1, what did you do next?

Ryan - So some of the cells are still there, they just look more aged, right? They don't have the same phenotype, the state, the molecular state as measured by single cell RNA sequencing, is not there. So we hypothesized that if we could turn on LEF-1 in those older cells and keep it on, then it's possible that that transcription factor could sit on the DNA and be ready for a signal such as those that happen during wound healing. So we collaborated and found them a mouse that allowed us to control the expression of that transcription factor through transgenic technology, and it allowed us to express LEF-1 in those older fibroblasts. And when we did that, we created all different kinds of wounds at different time points. And, except for one time point, all regenerated with this enhanced stability that we hadn't seen before, with the erector pillys so that those wound hair follicles can even stand up if the mouse got cold.

Eva - Now that we know the importance of this factor, of LEF-1, what can we do with that information? Do you think one day we might have, you know, a cream that has Lef1 in it that we can rub on our skin if we get wounded?

Ryan - Right. I don't think you could put LEF-1 in a cream because transcription factors are notorious to be able to put inside of a cell. So the idea would be, and what we're trying to do now, is to understand what LEF-1 is doing in those special cell types, right? What are those downstream targets that LEF-1 is activating in response to a wound. And then I think we would actually want to try to understand this in humans.