Mouse model yields potential approach to EDS and wound healing
Therapies modulating extracellular matrix promoted healing in study
Researchers using a mouse model discovered two possible approaches for restoring more normal wound healing in classical Ehlers-Danlos syndrome (cEDS). Both help to beneficially modulate a network of molecules called the extracellular matrix (ECM).
The ECM is important for providing structure and support to cells and for promoting wound healing. The mouse model exhibited an abnormal and slow wound healing process reminiscent of what’s seen in cEDS patients, including a substantially disturbed ECM.
Blocking proteins called integrins that interact with the ECM using small molecule therapeutics or administering healthy fibroblasts, a type of connective tissue cell that produces components of the ECM, were both found to reverse wound healing defects in the mice.
“We demonstrate that rescue of ECM at the time of wounding with fibroblast transplantation or small molecules is sufficient to rescue the phenotype [profile] of defective wound healing in cEDS,” the researchers wrote. “Our observations have potential ramifications for designing therapeutic strategies for wound healing defects in cEDS.”
The study, “Modulating the Extracellular Matrix to Treat Wound Healing Defects in Ehlers-Danlos Syndrome,” was published in iScience.
EDS and wound healing
Most gene mutations known to cause Ehlers-Danlos syndrome affect the production of collagen, a group of proteins critical for providing structural support to the body’s tissues. Mutations in COL5A1 or COL5A2, encoding production of type V collagen, are the usual cause of cEDS.
A lack of this important structural protein gives rise to stretchy and fragile skin that’s easily bruised. Another hallmark symptom is impaired wound healing. When the skin of people with cEDS is damaged, it may take longer than usual to heal, leading to complications like infections and scarring. There aren’t currently any treatments for managing wound healing in cEDS, according to the researchers.
The ECM, of which collagen is a major component, is actively involved in repair processes that mediate proper wound healing, and its dysfunction could play a key role in the abnormal healing which characterizes cEDS. The cellular mechanisms underlying this process have not been thoroughly evaluated.
The California-based research team developed a mouse model for directly looking at the mechanisms of impaired wound healing in cEDS.
The mice were engineered so that Col5a1 could be deleted from skin fibroblasts at the precise time a skin wound occurred. This would enable the scientists to look directly at the active role of type V collagen right around the time of wound healing.
In response to a skin cut, these mutant mice showed an abnormal wound healing response very similar to what’s observed in people with cEDS, “thus making the model suitable for investigating the biology of wound healing defects in cEDS,” the researchers wrote. Specifically, while healthy mice exhibited wounds that grew smaller and closed up over time, the mutant mice had wounds that were significantly larger and slower to heal.
Regrowth of the top layer of skin (epidermis) was also significantly slowed, and evidence indicated that the ECM had failed to organize properly.
Gene activity analyses indicated that mice lacking Col5a1 after injury failed to increase activity of genes related to epidermis development as healthy mice did. There was also evidence that inflammation was exacerbated and collagen levels reduced.
Notably, the alpha-v beta-3 integrin protein was increased in the wounds of the mutant animals, consistent with elevations in various integrins that have been observed in cEDS patients and which have been implicated in ECM abnormalities.
When the mice were treated with a molecule called cilengitide to block that protein, abnormal wound healing was partially rescued.
The researchers wondered whether providing the mice directly with healthy fibroblasts would enable proper ECM formation and reverse the healing defects that were observed.
That was indeed the case. When fibroblasts from healthy animals were injected into the wounds of Col5a1-deficient mice, the wound healing process was accelerated and collagen levels were restored. Moreover, gene activity related to epidermis development was increased, and inflammatory responses were decreased.
The researchers proposed that both integrin-targeted therapeutics or fibroblasts, “could serve as potential therapeutic strategies for enhancing wound healing in cEDS.”
They noted, however, that while cilengitide was administered systemically to the mice, a more a topical treatment that could be placed directly on a skin wound is preferable for patients.
“These experiments need to be performed in order to translate this treatment modality as a potential therapeutic for patients,” the team concluded.
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