Two succeeding fibroblastic lineages drive dermal development and the transition from regeneration to scarring

Abstract

During fetal development, mammalian back-skin undergoes a natural transition in response to injury, from scarless regeneration to skin scarring. Here, we characterize dermal morphogenesis and follow two distinct embryonic fibroblast lineages, based on their history of expression of the engrailed 1 gene. We use single-cell fate-mapping, live three dimensional confocal imaging and in silico analysis coupled with immunolabelling to reveal unanticipated structural and regional complexity and dynamics within the dermis. We show that dermal development and regeneration are driven by engrailed 1-history-naive fibroblasts, whose numbers subsequently decline. Conversely, engrailed 1-history-positive fibroblasts possess scarring abilities at this early stage and their expansion later on drives scar emergence. The transition can be reversed, locally, by transplanting engrailed 1-naive cells. Thus, fibroblastic lineage replacement couples the decline of regeneration with the emergence of scarring and creates potential clinical avenues to reduce scarring.

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

“…Further, we have shown that the back-skin undergoes a change in fibroblast cell lineage composition from ENF-predominant to EPF-predominant during skin development. The succession of these two fibroblast lineages leads to a phenotypic shift in the skin's response to injury, from fetal regeneration to adult scarring [14]. Similarly, by genetic fate mapping, Dulauroy and colleagues have shown that transient expression of a disintegrin and metalloprotease domain 12 (ADAM12) identifies a subset of perivascular PDGFRα + fibroblasts that overproduce collagen during scarring in dermis and muscle [16].…”

A multiscale hybrid mathematical model of epidermal‐dermal interactions during skin wound healing

“…In terms of its limitations, our model does not consider potential heterogeneity in skin fibroblast populations, and the possibility that different fibroblast subtypes can respond differently to signalling cues and exert distinct effects on wound healing. Indeed, several recent studies have identified distinct populations of mouse skin fibroblasts with distinct roles in ECM deposition during development and wound healing. Rinkevich et al identified two populations of mouse skin fibroblasts: En1 (Engrailed homeobox 1)‐negative and En1 ‐positive cells.…”

“…The former are abundant during skin development, and the latter increase in numbers late in adulthood and predominantly deposit collagen and remodel ECM during wound healing. Developmental change in En1 ‐positive vs En1‐ negative fibroblast abundance affects scarring outcomes in skin wounding experiments. Driskell et al.…”

Repair, regenerate and reconstruct: meeting the state-of-the-art

“…Several laboratories are exploring the emergence of scars in mammalian skin and its reversion to scarless regenerated tissue. Yuval Rinkevich (Helmholtz Center, Munich, Germany) showed that the shift from scarring to scarless regeneration is caused by a change in fibroblast compositions in the skin (Jiang et al, 2018). The dermal lattice in developing skin originates from engrailednegative fibroblasts, whereas it is later colonized by engrailedpositive cells that promote fibrotic scar formation.…”