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Wound healing in adults commonly occurs via fibrotic scar formation rather than tissue regeneration, which is associated with an absence of hair follicles and cutaneous fat amongst other things.

The authors of the publication reviewed in this spotlight observed that large wounds in mice often had areas of hair follicle regeneration and that adipocytes could be found exclusively at these haired scar regions at later time points (d23 onwards).

Dermal cells harvested from haired wounds, but not those from hairless wounds, consistently differentiated into adipocytes in vitro. The authors hypothesized that the cellular origin of these adipocytes was a major scar-contributing cell type, the myofibroblast.

This was confirmed by lineage tracing and functional knock-out studies during wound healing. Conditional knockout of PPARγ, a stimulator of adipogenesis, within myofibroblasts had no impact on hair regeneration within wounds but significantly reduced the presence of adipocytes. Importantly, this knock-out did not affect fat deposits outside of the wound.

The authors then went on to elucidate the molecular mechanism of this lineage reprogramming and discovered a critical role for ZFP423, a transcription factor involved in adipose differentiation during embryogenesis. ZFP423 was expressed in dermal cells juxtaposed to new hair follicles prior to onset of adipocyte differentiation, initially increasing in numbers before decreasing coincidentally with the increase of mature adipocytes.

Transcriptional data also suggested an activation of the BMP signaling pathway within the dermis upon adipocyte differentiation, which coincided with increased ZFP423 expression. Inhibition of the BMP pathway prevented adipocyte regeneration in haired wounds. In vitro BMP4 treatment and co-culture with human scalp hair follicles promoted the conversion of human keloid fibroblasts into adipocytes.

Adipocytes are known to have a positive impact on wound healing, in comparison to myofibroblasts that contribute to scarring. This publication highlights a novel opportunity to influence wound healing through BMP signaling and hair regeneration to convert detrimental myofibroblasts into adipocytes.