Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing
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Curated by eLife
Evaluation Summary:
The authors identify a novel compound called Dwn1 that suppresses the expression of Npas2, a key gene that delays wound healing. In doing so, they identify a novel treatment strategy for incisional surgical wounds that may have broader application to the treatment of scars in general.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)
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Abstract
Attempts to minimize scarring remain among the most difficult challenges facing surgeons, despite the use of optimal wound closure techniques. Previously, we reported improved healing of dermal excisional wounds in circadian clock neuronal PAS domain 2 ( Npas2 )-null mice. In this study, we performed high-throughput drug screening to identify a compound that downregulates Npas2 activity. The hit compound (Dwn1) suppressed circadian Npas2 expression, increased murine dermal fibroblast cell migration, and decreased collagen synthesis in vitro. Based on the in vitro results, Dwn1 was topically applied to iatrogenic full-thickness dorsal cutaneous wounds in a murine model. The Dwn1-treated dermal wounds healed faster with favorable mechanical strength and developed less granulation tissue than the controls. The expression of type I collagen, Tgfβ1, and α-smooth muscle actin was significantly decreased in Dwn1-treated wounds, suggesting that hypertrophic scarring and myofibroblast differentiation are attenuated by Dwn1 treatment. NPAS2 may represent an important target for therapeutic approaches to optimal surgical wound management.
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Evaluation Summary:
The authors identify a novel compound called Dwn1 that suppresses the expression of Npas2, a key gene that delays wound healing. In doing so, they identify a novel treatment strategy for incisional surgical wounds that may have broader application to the treatment of scars in general.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)
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Reviewer #1 (Public Review):
Authors found that Dwn1 suppressed circadian Npas2 expression, and increased fibroblast cell migration, and decreased collagen synthesis in vitro. Then, they applied Dwn1 to full-thickness murine wounds and showed that Dwn1-treated dermal wounds healed faster and developed less granulation tissue than the controls. It was suggested that Dwn1 treatment might control the hypertrophic scaring .
Authors showed the effectiveness in vito, but their in vivo skin defect model had too narrow skin defects to compare the scarring and the observation period seemed to be short.
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Reviewer #2 (Public Review):
Building upon prior work in which the authors identified Npas2 as a key suppressor of wound healing, they perform a high-throughput drug screen to identify a compound called Dwn1 as a pharmacologic strategy to improve wound healing. A major strength of this paper is that it translates recent genetic work to a potential new therapy for wounds. The data support their conclusions that Dwn1 should be investigated further in as a new treatment. This paper also implicates peripheral circadian biology to the process of wound healing. Thus, this work has the potential to further unveil how circadian biology intersects with wound biology. They have also developed a unique way to assess linear incisional wounds which may be a useful technique for other investigators.
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