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Page 6 of 18 Wilgus. Plast Aesthet Res 2020;7:54 I http://dx.doi.org/10.20517/2347-9264.2020.150

Because there was an adequate number of immune cells in the lymph nodes, the authors speculated that
the reduced immune cell numbers present in the skin was due to a deficiency in homing signals. Indeed,
they found reduced levels of chemokines such as CCL17, CCL21, and CCL27 in fetal skin.

Other types of scarless wounds
[62]
Besides fetal skin, scarless healing has also been described in mucosal tissues, such as the oral mucosa .
There is also evidence that oral mucosal wounds have a blunted inflammatory response compared to other
[63]
tissues that heal with scarring. In a mouse model, Szpaderska et al. showed fewer macrophages, less
myeloperoxidase (a marker of neutrophil presence), and lower pro-inflammatory cytokine production in
oral mucosal wounds (scarless) compared to cutaneous wounds (scar-forming). Similarly, in a porcine
[64]
model, Mak et al. compared oral and skin wounds in red Duroc pigs and found reduced macrophage and
mast cell numbers in oral wounds, which also displayed accelerated resolution of inflammation. In healthy
[65]
human oral and skin tissue (uninjured), fewer neutrophils and macrophages have been reported . Global
transcriptome analysis by multiple groups suggests that several pro-inflammatory genes and regulatory
pathways are suppressed or are less persistent in oral mucosal wounds compared to skin wounds [66,67] .

Scarless healing has also been documented in a unique mouse species, the African spiny mouse (Acomys).
Acomys was shown to completely regenerate and heal without scarring in response to large dorsal skin
[68]
wounds . Follow up studies compared transcription profiles of scar-forming wounds from standard
laboratory mice (Mus) and regenerative wounds from Acomys, and showed Acomys wounds had a
[69]
diminished cytokine/chemokine response . Acomys has also been reported to be neutropenic (reduced
blood neutrophils) and have less pronounced macrophage recruitment to wounds compared to Mus
[70]
strains . These results fit the general theme observed with scarless oral mucosal and fetal wounds, which
have a dampened inflammatory response compared to wounds that heal with scars.

FUNCTIONAL DATA LINKING INFLAMMATION AND SCARRING
In addition to correlative data, which generally link higher inflammatory mediator levels and/or elevated
inflammatory cell numbers in a wound to more abundant scar formation, there are also functional data
supporting a role for inflammation in promoting scar formation. These include studies showing that
inflammatory cells or inflammatory mediators stimulate scar tissue/collagen production as well as studies
showing that depletion or knockdown of inflammatory components reduces scar formation.

Inflammatory cells
Mast cells
Two general approaches have been used to study the function of mast cells in wound healing and scar
formation: treatment with mast cell stabilizing drugs and examination of mast cell-deficient mouse strains.

Drugs that act as mast cell stabilizers, which prevent mast cell degranulation, have been used in animal
models of wound healing to study the importance of mast cells in scar formation. By preventing mast
cell degranulation, these drugs inhibit the release of pre-stored mediators present within the granules.
Disodium cromoglycate (also known as cromolyn) has been shown to reduce collagen content in a
[71]
rat model when injected directly into wounds . Systemic treatment with disodium cromoglycate has
also been shown in a mouse excisional wound model to reduce pro-inflammatory cytokine levels and
myeloperoxidase levels (commonly used to estimate the presence of neutrophils) at early time points post-
injury, while reducing scar size and normalizing collagen architecture/collagen fibril density at later time
[72]
points . Another study showed that oral administration of the mast cell stabilizer ketotifen reduced
wound contraction and collagen deposition, causing thinner, less dense collagen fibrils to be produced in a
[73]
red Duroc pig model .