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Reprogramming fibroblasts could result in scar-free wound healing, suggests study in mice

STANFORD, CA (US), April 2021 — Researchers have determined a way to potentially minimize or eliminate scarring in wounded skin, by further decoding the scar-promoting role of a specific class of dermal fibroblast cells in mice. By preventing these cells from expressing the transcription factor Engrailed-1 (En-1), Shamik Mascharak, anM.D.-Ph.D. student at Stanford University School of Medicine,and colleagues reprogrammed these cells to take on a different identity, capable of regenerating wounded skin – including the restoration of structures such as hair follicles and sweat glands that are absent in scarred skin tissue.

With further development and testing, their discovery could lead to therapies to reduce or completely avoid scarring in human patients.

Fibroblast cells that express En-1 – called Engrailed-1 lineage-positive fibroblasts (EPFs) – have been implicated in scar formation, but the precise underlying mechanisms have remained unknown.

The Mascharak team noted that, while the progenitor cells of EPFs do not express En-1 in newborn and infant mice, fully functional EPFs are a known feature of skin wounds in adult mammals. Accordingly, they set out to determine whether EPFs proliferate in mammals as they age, or whether they expand locally at wound sites in response to new damage.

Through a series of cell transplantation and genetic tracing experiments to explore the expression of En-1 in wounded mouse skin, the team found evidence for a closely related type of cells, called Engrailed-1 lineage-negative fibroblasts (ENFs), that do not express En-1. Mechanical signals activate the canonical Yes-associated protein (YAP) pathway in ENF cells, which in turn prompts the cells to begin expressing En-1, completing their transformation to scar-promoting EPF cells. By blocking the YAP pathway by either administering the inhibitor compound verteporfin or knocking out the YAP gene, Mascharak and his team encouraged these cells to retain their identity as ENFs, enabling the cells to rebuild the wounded skin, complete with regenerated sweat glands and hair follicles.

"Tissue scarring is a leading cause of morbidity and mortality worldwide," noted Piotr Konieczny, Ph.D., and Shruti Naik, Ph.D., in a related “Focus” item in the journal Science, which published the study’s findings. "The findings by Mascharak et al. thus hold great promise not only for [anti-scarring] therapies but also for the simultaneous activation of the skin's regenerative properties."

Engrailed-1 activation in skin fibroblasts drives scarring.

After injury, a subset of dermal fibroblasts activates Engrailed-1 (En1) to contribute to scarring (left). Inhibiting postnatal En1activation, either directly (by ablating En1-activating cells) or indirectly (by blocking mechanical signaling with verteporfin), promotes skin regeneration by En1 lineage–negative fibroblasts, with full recovery of normal hair follicles, glands, matrix ultrastructure, and mechanical strength. Green cells, En1 lineage–positive fibroblasts; red cells, En1 lineage–negative fibroblasts. Image courtesy of Shamik Mascharak et al.


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DOI: 10.1126/science.aba2374