The skin is an intricate structure composed of the epidermis and dermis, inclusive of subcutaneous fat, or a dermal adipocyte layer.
Image Credit: Jacob Lund/Shutterstock.com
The skin is consistently challenged by the environment through the penetration of harmful UV rays, invasion of harmful pathogens and the evaporation of water. Perhaps, most importantly its protects the underlying organs necessary for survival.
As a constant shield from the external environment, the skin is constantly exposed to potential injury so wound healing is a vital process, whilst other, lower organisms may have a refined system for complete tissue regeneration, humans are still left with scarring which can inhibit the effectiveness of the properties of the skin.
If there is damage from extensive burns it can have a devastating cosmetic and psychological effect. Thus, having an understanding of skin regeneration and wound healing is highly valuable.
Wound repair in mammals and regenerative capabilities.
There are several events involved in full-thickness wound repair in mammalian skin. These typically occur in three overlapping stages:
- Inflammation
- Tissue formation
- Tissue remodeling
From this, the normal outcome is scar tissue composed of non-physiologic dermal tissue masked by a smooth hairless epidermis. However, we have seen within many examples found in nature, there is complete regeneration of the skin, rather than scarring.
Examples, where this takes place, include adult fish, urodele skin and fetal mammalian skin up to the end of the second trimester.
Previous comparisons between fetal and adult mammalian wounds have led to the identification of distinct differences in fetal skin wounding such as a less robust immune response, lower levels of inflammatory cytokines and differences in matrix composition.
These differences may also be relevant to the outcomes of fish and urodele skin regeneration.
Remarkably, there are some adult mammals where the skin can regenerate fully after an injury such as punches through the ears of rabbits, spiny (non-scarring) mice, ear wounds in MRL mice and large skin wounds in C57B/L mice. This suggests it might not be solely a property of lower vertebrates and fetuses.
At present, much of the information about the differences between the scarring mouse and the non-scarring one is derived from cellular and genetic analyses and suggests that the involvement of proteins is more through implication rather than by direct observation.
Therefore a proteomic study would allow for the identification of proteins that favor scar-free healing.
Key findings from proteomic analysis
Proteomic analysis of skin regeneration is still in its infant stage, therefore there is limited data based on what has been found so far.
In Yoon et al’s study after comparing the non-scarring mice to scarring mice, they were able to identify that approximately 2000 proteins were identified at (mostly) similar levels.
However, the key finding was the distinct differences in the levels of ubiquitin-related enzymes, phosphorylation associated proteins, proteases, immunomodulators, and macrophage markers.
They found that there is enhanced degradation and synthesis of proteins through a major mechanism in a non-scarring mouse, particularly ubiquitination and phosphorylation which play key roles in signaling pathways utilized in tissue repair.
The data collected from these profiles allow for a more substantiated view of the microenvironment. Particularly interesting is the macrophage profiles which could enable different extra-cellular matrix microenvironments that can be critical to the outcomes of injury. In this particular case, fibrosis (thickening and scarring of tissue) was observed in the scarring mice and regenerative response in the non-scarring mouse.
Utilizing comparative and quantitative proteomics of cell-conditioned media-enabled scientists to further understand the roles of key molecules and processes from a translational perspective.
From using a bank of fetal and adult skin fibroblasts that were previously identified as mesenchymal stem cells, Gaetani et al. were able to identify secretome signatures relevant to therapeutic microenvironment modulation.
The proteins identified can directly modulate the extracellular matrix, angiogenesis which is key in scarless wound healing. The angiogenic trigger was corroborated in vitro with fetal skin MSC secretomes stabilizing and inducing the formation of capillary-like networks by endothelial cells.
References
- Takeo M, Lee W, Ito M. Wound healing and skin regeneration. Cold Spring Harb Perspect Med. 2015;5(1):a023267. Published 2015 Jan 5. doi:10.1101/cshperspect.a023267
- Yoon JH, Cho K, Garrett TJ, Finch P, Maden M. Comparative Proteomic Analysis in Scar-Free Skin Regeneration in Acomys cahirinus and Scarring Mus musculus. Sci Rep. 2020;10(1):166. Published 2020 Jan 13. doi:10.1038/s41598-019-56823-y
- Gaetani, M., Chinnici, C. M., Carreca, A. P., Di Pasquale, C., Amico, G., and Conaldi, P. G. ( 2018) Unbiased and quantitative proteomics reveals highly increased angiogenesis induction by the secretome of mesenchymal stromal cells isolated from fetal rather than adult skin. J Tissue Eng Regen Med, 12: e949– e961. doi: 10.1002/term.2417
Further Reading