1. Medicine
  2. Stem Cells and Regenerative Medicine

Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing

  1. Yoichiro Shibuya
  2. Akishige Hokugo  Is a corresponding author
  3. Hiroko Okawa
  4. Takeru Kondo
  5. Daniel Khalil
  6. Lixin Wang
  7. Yvonne Roca
  8. Adam Clements
  9. Hodaka Sasaki
  10. Ella Berry
  11. Ichiro Nishimura  Is a corresponding author
  12. Reza Jarrahy  Is a corresponding author
  1. University of California, Los Angeles, United States
https://doi.org/10.7554/eLife.71074
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Cite this article
  1. Yoichiro Shibuya
  2. Akishige Hokugo
  3. Hiroko Okawa
  4. Takeru Kondo
  5. Daniel Khalil
  6. Lixin Wang
  7. Yvonne Roca
  8. Adam Clements
  9. Hodaka Sasaki
  10. Ella Berry
  11. Ichiro Nishimura
  12. Reza Jarrahy
(2022)
Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing
eLife 11:e71074.
https://doi.org/10.7554/eLife.71074
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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, Tgfb1, and a-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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Article and author information

Author details

  1. Yoichiro Shibuya

    Department of Surgery, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0558-5154

  2. Akishige Hokugo

    Department of Surgery, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    ahokugo@mednet.ucla.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7097-3364

  3. Hiroko Okawa

    Weintraub Center for Reconstructive Biotechnology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Takeru Kondo

    Weintraub Center for Reconstructive Biotechnology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Daniel Khalil

    Department of Surgery, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Lixin Wang

    Department of Surgery, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Yvonne Roca

    Department of Surgery, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Adam Clements

    Department of Surgery, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Hodaka Sasaki

    Weintraub Center for Reconstructive Biotechnology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Ella Berry

    Department of Surgery, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Ichiro Nishimura

    Weintraub Center for Reconstructive Biotechnology, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    inishimura@dentistry.ucla.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3749-9445

  12. Reza Jarrahy

    Department of Surgery, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    rjarrahy@mednet.ucla.edu
    Competing interests
    The authors declare that no competing interests exist.

Funding

Annenberg Foundation

  • Reza Jarrahy

Plastic Surgery Foundation

  • Akishige Hokugo

UCLA (Innovation Fund)

  • Ichiro Nishimura

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Mone Zaidi, Icahn School of Medicine at Mount Sinai, United States

Ethics

Animal experimentation: All protocols for animal experiments were approved by the University of California Los Angeles (UCLA) Animal Research Committee (ARC# 2003-009) and followed the Public Health Service Policy for the Humane Care and Use of Laboratory Animals and the UCLA Animal Care and Use guidelines.

Version history

  1. Received: June 8, 2021
  2. Preprint posted: December 1, 2021 (view preprint)
  3. Accepted: January 14, 2022
  4. Accepted Manuscript published: January 18, 2022 (version 1)
  5. Version of Record published: January 25, 2022 (version 2)

Copyright

© 2022, Shibuya et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yoichiro Shibuya
  2. Akishige Hokugo
  3. Hiroko Okawa
  4. Takeru Kondo
  5. Daniel Khalil
  6. Lixin Wang
  7. Yvonne Roca
  8. Adam Clements
  9. Hodaka Sasaki
  10. Ella Berry
  11. Ichiro Nishimura
  12. Reza Jarrahy
(2022)
Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing
eLife 11:e71074.
https://doi.org/10.7554/eLife.71074

Share this article

https://doi.org/10.7554/eLife.71074

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