Wound Regeneration Deficit in Rats Correlates with Low Morphogenetic Potential and Distinct Transcriptome Profile of Epidermis

Abstract

Large excisional wounds in mice prominently regenerate new hair follicles (HFs) and fat, yet humans are deficient for this regenerative behavior. Currently, wound-induced regeneration remains a clinically desirable, but only partially understood phenomenon. We show that large excisional wounds in rats across seven strains fail to regenerate new HFs. We compared wound transcriptomes between mice and rats at the time of scab detachment, which coincides with the onset of HF regeneration in mice. In both species, wound dermis and epidermis share core dermal and epidermal transcriptional programs, respectively, yet prominent interspecies differences exist. Compared with mice, rat epidermis expresses distinct transcriptional and epigenetic factors, markers of epidermal repair, hyperplasia, and inflammation, and lower levels of WNT signaling effectors and regulators. When recombined on the surface of excisional wounds with vibrissa dermal papillae, partial-thickness skin grafts containing distal pelage HF segments, but not interfollicular epidermis, readily regenerated new vibrissa-like HFs. Together, our findings establish rats as a nonregenerating rodent model for excisional wound healing and suggest that low epidermal competence and associated transcriptional profile may contribute to its regenerative deficiency. Future comparison between rat and mouse may lend further insight into the mechanism of wounding-induced regeneration and causes for its deficit.

Biomechanical stress regulates mammalian tooth replacement via the integrin β1‐RUNX2‐Wnt pathway

“…Biomechanical forces participate in an organism's development (Shawky & Davidson, ). Mechanical heterogeneity is believed to result in hair regeneration in large excisional wounds (Davidson, ; Guerrero‐Juarez et al , ). In patients with aplastic lower second premolars, treatment of localized lower molar mesialization results in the development and eruption of wisdom teeth (Zimmer, ), indicating that mechanical stress from the adjacent tooth or jaw bone inhibits the development process of teeth.…”

Scars or Regeneration?—Dermal Fibroblasts as Drivers of Diverse Skin Wound Responses

“…Rather, the newly formed hairs are imbedded in fibrotic scar tissue and restricted to wound centers alone [107]. Moreover, WIHN is not observed in skin wounds that are inflicted in humans or even in rats [108]. Nevertheless, the strategies we have learnt from the WIHN model that inhibit Wnt/β-catenin signaling specifically in the dermis or boost Wnt/β-catenin signaling specifically in the epidermis may lead to new and effective antiscarring therapeutics.…”

Insights into the regeneration of skin from Acomys, the spiny mouse

“…This is the prevailing view of the result of a variety of types of damage—physical removal, surgery, tearing, chemical or thermal burning—as evidenced by our own bodies which accumulate such wounds throughout life. That is also the case for the typical laboratory mammal—rats and mice—which also heal skin damage with a hairless scar. However, this may not necessarily be the case for all mammals and it is perfectly possible that skin regenerative ability has sporadically evolved, perhaps as an adaptive response to predation rather like the regenerative ability of the lizard tail.…”

“…It can be stimulated (produce more hairs) by a variety of methods—stimulating the Wnt pathway via disrupting the CXXC5‐dishevelled interaction, over‐expressing Wnt7a or setting up a positive feedback between FGF9 and Wnt . It is interesting to note that WIHN is not observed in the rat, a closely related rodent species …”