Luis Garza, a physician-scientist at Johns Hopkins University School of Medicine for over a decade, noticed a common issue when treating people with limb amputations at his clinic. They often had rashes and cuts at the amputation site where their skin could not withstand the high mechanical pressure of wearing prosthetics.1 The painful lacerations would deter patients from using their prosthetics, significantly affecting their quality of life.
“This sparked an interest to [find] a way to help people who have pressure at places that their body was not meant to have pressure,” said Garza.
Volar skin, found on the palms and soles of feet, is thicker than skin on the arms and legs and can withstand higher mechanical pressure.2 In recent research, Garza and colleagues showed that injecting fibroblasts from volunteers’ volar skin increased pressure-responsiveness of their non-volar skin that persisted for several months.3 The results, published in Science, demonstrate the therapeutic potential of volar fibroblasts to modify skin identity, suggesting an approach to prevent skin pressure-induced damage.
It is nice to see the study show that transplantation changes skin traits, said Ryan Driskell, a skin biologist at Washington State University, who was not associated with the study. “It doesn’t surprise me per se, because the theory was always there.”
Experiments in the 1960s had revealed that the fibroblast-containing dermal compartment of the skin determines the identity of the outermost skin layer, the epidermis, in mammals. When researchers had mixed the dermis of hamsters and epidermis of guinea pigs and grafted it into a host, they found that the graft showed properties of hamster skin.4
For their current study, Garza and his team built on this and more recent work reporting that fibroblasts have positional memory.5 “We realized we could take the fibroblasts out of a person and they would maintain their identity in culture,” said Garza. “And when we put them back in, they should be the more dominant feature to control tissue identities.”
Before the researchers could transplant fibroblasts, they characterized differences in volar and non-volar fibroblasts under pressure. They isolated and grew fibroblasts collected from volunteers’ scalps (non-volar skin) and soles (volar skin) and subjected these cells to high pressure by adding a viscous chemical. They found that fibroblasts from the soles showed higher rates of migration and activation of different genes, specifically those that help withstand mechanical pressure, compared to those from the scalp.
After establishing that volar and non-volar fibroblasts behaved differently under pressure, the researchers investigated whether fibroblasts influenced epidermal identity in skin constructs. They engineered three-dimensional scaffolds containing either scalp or sole fibroblasts. On combining these with epidermal cells from non-volar skin, sole fibroblasts induced volar features such as thicker epidermis and expression of volar epidermal markers.
Encouraged by these observations, the team decided to test the therapeutic potential of volar fibroblasts in a Phase 1 clinical trial. They injected fibroblasts isolated from participants’ scalps or soles into the non-volar skin of their thighs. Injecting cells from a person into their own body prevents the complications of transplant rejection, noted Garza.
Histological analysis of skin biopsied five months after injecting fibroblasts from the soles revealed that the skin showed volar features, including increased epidermal thickness, dermal collagen fiber length, and dermal elastin expression.
To better characterize the changes that occurred in the skin, the researchers performed RNA sequencing on tissues biopsied between two weeks and 17 months after fibroblast injections. This confirmed the expression of genes associated with volar skin identity at sole fibroblast injection sites.
“We were really excited because you never know that all that basic foundational work is accurate. But nobody ever really tried this, especially in people, and not really in mice either,” said Garza.
“This is how one would dream to use fibroblasts,” said Driskell. “But this has implications beyond just the skin.” Other organs like the lungs, intestines, and kidneys also contain fibroblasts.6 Understanding fibroblast population heterogeneity in such organs can inform new therapies, noted Driskell.
Garza and his team’s immediate goal is to optimize therapy to enhance the extent to which skin identity changes after injecting fibroblasts and proceed towards the next phase of clinical trials. Cell and gene therapy is the new arm of medicine, after surgery and pharmacology, according to Garza. “Our work is part of the effort trying to move this third arm of medicine into a reality.”
