LUis Garza, a medical scientist at the Johns Hopkins University School of Medicine for more than a decade, noticed a common problem while treating amputee patients in his clinic. They often develop rashes and cuts at the site of amputation because their skin cannot withstand the high mechanical stress of wearing a prosthetic limb.1 Painful lacerations can prevent patients from using prostheses, seriously affecting their quality of life.
“This arouses interest in [find] It’s a way to help people take stress in places in their body where it shouldn’t be,” Garza said.
The volar skin of the palms and soles of the feet is thicker than the skin of the arms and legs and can withstand higher mechanical stresses.2 In recent research, Garza and colleagues showed that injecting fibroblasts from volunteers’ volar skin enhanced the stress reactivity of non-volar skin that could persist for months.3 The results were published in sciencedemonstrated the therapeutic potential of palmar fibroblasts to alter skin properties, proposing a method to prevent skin pressure-induced damage.
Ryan Driskell, a dermatologist at Washington State University who was not involved in the study, said he was pleased to see the study showing that transplantation can change skin characteristics. “That in itself doesn’t surprise me because the theory has always been there.”
Experiments in the 1960s showed that the dermal region of skin, which contains fibroblasts, determines the identity of the outermost skin layer (epidermis) in mammals. When the researchers mixed hamster dermis and guinea pig epidermis and transplanted them into a host, they found that the grafts exhibited the properties of hamster skin.4
In their current study, Garza and his team built on this research and recent reports that fibroblasts have positional memory.5 “We realized that we could take fibroblasts out of the human body and they would maintain their identity in culture,” Garza said. “When we put them back in, they should become more dominant features that control tissue identity. “
Before the researchers transplanted the fibroblasts, they characterized the differences between volar and non-volar fibroblasts under stress. They isolated and cultured fibroblasts collected from volunteers’ scalps (non-volar skin) and soles (volar skin) of their feet and subjected the cells to high pressure by adding sticky chemicals. They found that compared with fibroblasts in the scalp, fibroblasts in the soles of the feet showed higher rates of migration and activation of different genes, particularly those that help withstand mechanical stress.
After determining that volar and non-volar fibroblasts behaved differently under stress, the researchers investigated whether fibroblasts could influence epidermal properties in skin structure. They designed three-dimensional scaffolds containing fibroblasts from the scalp or soles of the feet. Combining these with epidermal cells from non-volar skin, plantar fibroblasts induce volar characteristics such as thicker epidermis and expression of volar epidermal markers.
Encouraged by these observations, the research 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 of their feet into the nonvolar skin of the thighs. Garza noted that injecting human cells into one’s own body could prevent the complications of transplant rejection.
Histological analysis of skin sections five months after injection of fibroblasts from the sole of the foot revealed volar features of the skin, including increased epidermal thickness, dermal collagen fiber length, and increased dermal elastin expression.
To better characterize the changes occurring in the skin, the researchers performed RNA sequencing on tissue biopsied from two weeks to 17 months after the fibroblast injection. This confirmed the expression of genes associated with volar skin properties at the site of plantar fibroblast injection.
“We’re really excited because you never know when all the basic groundwork is going to be accurate. But no one has really tried this, especially in humans, and it hasn’t really been tried in mice,” Garza said. .
“This is how people dream of using fibroblasts,” Driskel said. “But it doesn’t just affect the skin.” Other organs such as the lungs, intestines and kidneys also contain fibroblasts.6 Driskel noted that understanding the heterogeneity of fibroblast populations in these organs could inform new treatments.
The immediate goal for Garza and his team is to optimize the treatment to increase the extent of changes in skin properties following injection of fibroblasts and move into the next phase of clinical trials. Garza said cell and gene therapy is a new branch of medicine following surgery and pharmacology. “Our work is part of an effort to make third medicine a reality.”
