TY - JOUR
T1 - Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing
AU - Shibuya, Yoichiro
AU - Hokugo, Akishige
AU - Okawa, Hiroko
AU - Kondo, Takeru
AU - Khalil, Daniel
AU - Wang, Lixin
AU - Roca, Yvonne
AU - Clements, Adam
AU - Sasaki, Hodaka
AU - Berry, Ella
AU - Nishimura, Ichiro
AU - Jarrahy, Reza
N1 - Funding Information:
This work was generously supported in part by the Annenberg Fund for Craniofacial Surgery and Research at UCLA (RJ), the Plastic Surgery Foundation (AH), and the UCLA Innovation Fund (IN). We thank Dr Robert Damoiseux, Director of UCLA MSSR, for his consultation for high-throughput drug screening. We also thank the Translational Pathology Core Laboratory (TPCL) in the UCLA Department of Pathology and Laboratory Medicine for histology preparation and immunohistochemistry, and Dr Chase Linsley in the UCLA Bioengineering for Instron test guidance.
Publisher Copyright:
© Shibuya et al.
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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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U2 - 10.7554/eLife.71074
DO - 10.7554/eLife.71074
M3 - Article
C2 - 35040776
AN - SCOPUS:85123740514
SN - 2050-084X
VL - 11
JO - eLife
JF - eLife
M1 - e71074
ER -