ISCRM Faculty Shine a New Light on Scarring

By Thatcher Heldring

October 12, 2018

Collaboration is the engine of scientific progress at UW Medicine and at the Institute of Stem Cell & Regenerative Medicine (ISCRM), where 130 researchers are developing stem cell-based approaches to treat diseases affecting nearly every organ and system in the human body.  

So, exactly what does it look like when two clever minds probing questions about everyday biological functioning team up for the greater good?

Dr. Cole DeForest is an Assistant Professor in Chemical Engineering and an ISCRM faculty member

For Dr. Cole DeForest and Dr. Jen Davis, the story is about shedding new light – literally – on the cellular processes essential for an underappreciated aspect of human health – scarring.

Dr. DeForest is an Assistant Professor in UW’s Department of Chemical Engineering. Dr. Davis is an Assistant Professor of Bioengineering and Pathology at UW Medicine. Both are core faculty members at ISCRM.

Rodent heart cells magnified 40X and stained with immunofluorescent dyes to show the conversion of fibroblasts into myofibroblasts (scar-forming cells)

Scarring is vital for wound healing, whether the injury occurs on the outside of the body or internally, say, to an organ. In their investigation, DeForest and Davis are looking closely at the behavior of fibroblasts, cells that are responsible for building the scaffolding matrix that give organs their structure and shape.  

DeForest and Davis want to know what happens to these fibroblasts – and the scaffoldings they create – in response to the pulsatile forces that accompany each heart beat, pumping blood to cells throughout the body.  

“There is a growing appreciation that cyclic mechanics play an important role in guiding cell fate,” says DeForest. “Every time the heart pumps, our tissues undergo transient minor stiffening that can alter biological function in largely unknown ways. We are looking into how these cyclic tissue stiffening events impact scarring.”  

To answer those questions, DeForest’s lab has developed synthetic environments, known as hydrogels, that recreate critical properties of actual human tissue. In a paper published recently by Advanced Biosystems, DeForest and Davis detail how they created a synthetic culture environment whose stiffness could be reversibly tuned with light, and then used these biomaterials to investigate the effects of cyclic mechanics on fibroblast cell function.

“Our excitement is really two-fold,” explains DeForest. “First, we were able to create materials who stiffness can be cyclically controlled on a timescale similar to what is presented in the body. Second, we used these materials to show that such dynamic network mechanics play a role in signaling fibroblasts to become scar-forming myofibroblast cells.”

Dr. Jennifer Davis is an Assistant Professor in Pathology and Bioengineering and an ISCRM faculty member

Specifically, DeForest and Davis exposed the materials containing encapsulated cells to blinking light patterns, like a disco ball, causing a stiffening and softening cycle that induced the cells to undergo a process called transdifferentiation, a behavioral change that gives a cell a new function. This reprogramming can occur naturally in tissue or be coaxed by cues presented within a synthetic environment like the one developed in DeForest’s lab.

For Davis, who is researching heart regeneration, this window into the nature of scarring has profound implications. “We’re trying to understand the properties of scar growth so that we can modulate it. We know that the more scarring you have, the less regeneration you’re going to get. So, our view is if you can control the scarring, you can improve it, or even block it from happening in the first place.”

Davis sees other exciting applications for the synthetic system that she and DeForest used to study the effects of cyclic stiffening on fibroblasts. “There are so many uses for what Cole has developed that are fundamental to ISCRM. For instance, a major barrier in muscular dystrophy research has been the inability to recreate a dystrophic phenotype in vitro because in conventional cell culture systems muscle cells aren’t exposed to repeated stress and strain. I could envision exposing patient-derived dystrophic muscle cells to these tunable scaffolds and uncovering the primary molecular regulators of dystrophic disease.”

Down the road, Davis and DeForest also see implications for wound healing that could improve life for soldiers or people suffering from diabetes. At the root of their enthusiasm, though, is a shared appreciation for the spirit of collaboration at ISCRM.

“My lab excels at building tunable biomaterials,” says DeForest. “But we really benefit from all the people at ISCRM, encompassing experts from so many areas, to help realize the full potential of these systems.”

“Our work is in two entirely divergent areas,” adds Davis. “I would never have been able to build that material, even though I was desperate for something like it.”