Fibrosis contributes to over 45% of all deaths. New UA research aims to stop it from forming

After certain kinds of injuries or wounds — think heart attacks, burns and tendon tears, among others — scar tissue can form to help the healing process. But that scar tissue can lead to fibrosis later on, which can be a problem in those patients.

New research from the University of Arizona, though, is looking for ways to prevent that from happening.

Dr. Kellen Chen is an associate professor in the Departments of Surgery and Biomedical Engineering at UA and runs a research lab focused on investigating tissue fibrosis and promoting regeneration. He’s also the co-author of a study on this published in Nature Biomedical Engineering.

Chen spoke with The Show more about this, and Chen started with scar tissue and its role in healing.

Full conversation

KELLEN CHEN: Yes. So in in humans, you know, tissue injury can occur in a variety of different ways, but it almost always results in fibrosis and scar formation. So during the process of tissue healing, the body builds scar tissue through an overactive wound healing response. And this is in part mainly to try and plug up any injury that has occurred.

But what happens is it leads to significantly impaired organ function. And so fibrosis causes a lot of morbidity and mortality and contributes to almost 45% of all deaths in the United States.

MARK BRODIE: So it sounds like the key then would be to make sure that the scar tissue that is necessary for healing is there, but in a perfect world, maybe just enough to heal what needs to be healed and not so much that it causes problems later on.

CHEN: Yes, exactly. Well said. So I think in response to an injury, the body has to do something. So right now, what it's mostly doing is creating too much scar tissue. And if we could tune that back, that would be great for promoting the right function.

And then on the other end of it, as sort of regenerative biologists, we're interested in actually now maybe even convincing the body to regenerate and create new tissue that mimics exactly what your old tissue was like.

BRODIE: Well, and that sounds like what the research that you've been working on is doing. Is that right?

CHEN: Yes, exactly.

BRODIE: So how exactly does that work?

CHEN: Right. So currently, there's, you know, effective treatment strategies to prevent exuberant fibrosis have not been developed. So there's an urgent need to find ways to mitigate this condition or even shift it toward a regenerative phenotype.

And so what we've been able to do is actually identify a specific immune cell type that circulates throughout your body and it seems to act as one of the primary drivers of fibrosis across across the body. And what we found basically in the study is that by specifically targeting those cells, you can then basically influence all the other cells in part of this healing process that are also dysfunctional and convert them to become in a sort of less scarring or even pro-regenerative manner.

BRODIE: So does that mean that you're kind of turning that tissue back into the kind of tissue that used to be in wherever the injury happened?

CHEN: So these cells respond to a process called mechanical signaling. So I guess before I get into all those details, in essence, whenever humans undergo an injury, they upregulate these mechanical stress profiles. And the reason that we upregulate those is because in order for us to have everyday motion and move, your tissues undergo that sort of normal stress and strain. So that's good for us to move normally, but when there's an injury it actually can act in the opposite direction.

So what we found basically is that by targeting those pathways in injured tissue, we're able to promote regeneration and have the tissue go from that dysfunctional scar into the proper tissue that you need. So that can work if you wanted to, for example, inject some sort of therapy in the different organs. But what's really exciting about this study is that these cells naturally are circulating throughout your body.

So instead of having to sort of target each organ individually and specifically, we can now target these cells, which are sort of the upstream drivers of this process, and have them beneficially affect the entire body all at once.

BRODIE: Are you able to take cells from different parts of the bodies and kind of send them to where the injury happened, where they might be needed?

CHEN: Yeah, that's a great question. So after any of these injuries I had mentioned before, such as a heart attack, a tendon tear, or a burn injury, or even more, the body responds by ... as you know, bleeding. So that blood is what delivers these cells throughout the body. So these immune cells are naturally circulating throughout your bloodstream.

And we've already known for a long time that after injury, you know, you need to have bleeding so that these immune cells come and sort of start this healing process. And what we've identified is that a certain subset of those cells that do go toward the injury are also very responsive to the mechanical environment and that by targeting those, you're able to still have the normal process go on, but that you're able to reduce the fibrosis that occurs.

BRODIE: How do you target those cells and get them to sort of go where they need to go and do what you want them to do?

CHEN: In the study, a lot of these studies were performed in animals. So in animals, what you're able to first do is you're able to genetically target those cells by creating a genetically modified mouse strain. So in those mice, we found that by specifically removing these cell types in the mouse, in the mouse's bloodstream, they exhibited much reduced fibrosis and even promotion of regeneration. So when we looked at the normal tissue architecture, it was much more similar to your normal tissue compared to a fibrotic scar, which has a lot of collagen, it's very thick and just feels very stiff.

What we've also done in human cells, so we haven't obviously tested these cells in humans yet, but we've been able to isolate these cells out from humans and use an inhibitor of these pathways on the immune cells to downregulate this behavior and found that that specifically then also promotes sort of reduction in fibrosis in a dish.

BRODIE: So then when you get to the point where this is applicable in patients, in human patients, would that be some kind of medication they take to sort of target these cells to go and do this sort of thing in these particular areas? Is there another way to make that happen?

CHEN: There's two ways we envision this happening for humans. So one is that there's already a lot of immunotherapies out there. We're envisioning something potentially similar where you could take the patient's own blood and find these cells and then treat the cells with an inhibitor so that the cells do not become overactive and then take these cells and give them back to the patient. And then this would reduce those fibrotic profiles.

Another thing we can do is I mentioned these cells respond to mechanical signals. Well, there are certain mechanical signaling proteins that are only on these immune cells, so they're not in any of the other cells. So if we gave the patient a treatment in their bloodstream that only targeted those cells, we'd have the same effect without accidentally targeting some of the other cells, your normal cells in your body.

BRODIE: Assuming that things continue going in a positive direction, how big of a dent do you think this could put in the problem of scar tissue causing all of these various problems in all of these various different parts of the bodies that people have?

CHEN: Of course, as a scientist, you know, it's always hard to know exactly, but as I mentioned, you know, fibrosis does contribute to over 45% of all deaths in the United States. And we're all very familiar with heart attacks and burn wounds and tendon tears and also, you know, liver failure. So this could potentially have very far-reaching impacts. We've already identified that these cells are specifically also upregulated in the fibrotic liver tissue. And so current efforts in our lab are to try to identify this in just a variety of other organ systems so that we can have evidence to test it all over.

BRODIE: All right, that is Kellen Chen, an associate professor in the University of Arizona College of Medicine, Tucson. Kellen, thanks so much. I really appreciate it.

CHEN: Thank you very much.