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.
Highlights
Postsurgical hypertrophic scarring is relatively frequent, even with careful surgical care aimed at reducing inflammation, angiogenesis and fibrogenesis [1]
Segmented color analysis of Masson’s trichrome (MT)-stained sections (Fig. 1-supplement 1) 118 revealed that collagen fiber density was significantly higher in the peripheral zones than in the central zones (Fig. 1f)
We are confident that the peripheral zone in our model is representative of dermal and subcutaneous wound healing and not the morpho-functional influences of deeper muscle layers that have been described in murine models [35]
Summary
Postsurgical hypertrophic scarring is relatively frequent, even with careful surgical care aimed at reducing inflammation, angiogenesis and fibrogenesis [1]. Hypertrophic scarring results from the excessive deposition of collagen extracellular matrix (ECM) during wound healing. Mathematical modeling [10] and on-chip wound healing assays [11] suggest that the activation of dermal fibroblast migration plays a critical role in wound closure and the degree of scarring. The finding that circadian dysregulation is associated with a wide range of diseases [19,20], clock genes and the products of their expression have become targets in the growing research and clinical field of chronotherapy [21,22]. Through a high-throughput screening process, we identified a small molecule compound that downregulates Npas expression in dermal fibroblasts and results in the accelerated healing of dorsal incisional wounds in mice with minimum scarring
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