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Inhibition of EN1 Activity Heals Skin Injuries without Scarring in Mice

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Posted 03 May 2021 - 10:11 AM

There is an interesting history of accidental discoveries regarding exceptional regeneration in mammals, such as the MRL mice that are capable of regenerating the ear tags and notches that researchers use to track mice through experiments, thereby causing some confusion. Researchers have since then spent time on attempts to identify important mechanisms by which mammalian regeneration takes the path of scarring, rather than the path of regrowth. The discovery noted here is an interesting one. The scientists involved have established a good proof of concept based on a regulator of scarring, EN1. When suppressed this leads to the complete regeneration of skin injuries without scar formation.

Skin wounds generally heal by scarring, a fibrotic process mediated by the Engrailed-1 (En1) fibroblast lineage. Scars differ from normal unwounded skin in three ways: (i) They lack hair follicles, sebaceous glands, and other dermal appendages; (ii) they contain dense, parallel extracellular matrix fibers rather than the "basket-weave" pattern of uninjured skin; and (iii) as a result of this altered matrix structure, they lack skin's normal flexibility and strength. A successful scar therapy would address these three differences by promoting regrowth of dermal appendages, reestablishment of normal matrix ultrastructure, and restoration of mechanical robustness. However, little is known about the cellular and molecular mechanisms blocking a regenerative healing response in postnatal skin, or whether these mechanisms can be bypassed by modulating specific fibroblast lineages.

We asked whether scarring fibroblasts are derived purely from expansion of existing En1 lineage-positive fibroblasts present in unwounded skin, or whether En1 scar fibroblasts could arise de novo by activation of En1 expression in postnatal, En1 lineage-negative fibroblasts within the wound niche. We used fibroblast transplantation as well as transgenic mouse models to trace En1 expression in a spatiotemporally defined fashion. Next, we studied fibroblast responses to mechanical forces in vitro and in vivo to establish a mechanotransduction mechanism linking skin tension to postnatal En1 expression. Finally, we used chemical (verteporfin) and transgenic inhibition of mechanotransduction signaling to modulate En1 expression during wound healing.

Fibroblast transplantation and lineage-tracing studies reveal that En1 lineage-negative fibroblasts (ENFs) of the reticular (deep) dermis activate En1 in the wound environment, generating ~40 to 50% of scar fibroblasts. This phenomenon depends on mechanical cues. Comparison of ENFs with En1-expressing and En1 knockdown fibroblasts by RNA sequencing suggests that En1 regulates a wide array of genes related to skin fibrosis. In healing wounds, YAP inhibition by verteporfin blocks En1 activation and promotes ENF-mediated repair, yielding skin regeneration in 30 days with recovery of functional hair follicles and sebaceous glands. This suggests that modulation of En1 activation, whether direct or indirect, can yield wound regeneration.

Link: https://doi.org/10.1...science.aba2374

View the full article at FightAging

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