Cited by 115TGF-β signaling in diseasesInterstitial Lung Diseases and Idiopathic Pulmonary FibrosisWound Healing and Treatments

A positive feedback loop bi-stably activates fibroblasts

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Yeo, So-Young, Lee, Keun-Woo, Shin, Dongkwan, An, Sugyun, Cho, Kwang-Hyun, Kim, Seok-Hyung·2018·Nature Communications

Abstract

Although fibroblasts are dormant in normal tissue, they exhibit explosive activation during wound healing and perpetual activation in pathologic fibrosis and cancer stroma. The key regulatory network controlling these fibroblast dynamics is still unknown. Here, we report that Twist1, a key regulator of cancer-associated fibroblasts, directly upregulates Prrx1, which, in turn, increases the expression of Tenascin-C (TNC). TNC also increases Twist1 expression, consequently forming a Twist1-Prrx1-TNC positive feedback loop (PFL). Systems biology studies reveal that the Twist1-Prrx1-TNC PFL can function as a bistable ON/OFF switch and regulates fibroblast activation. This PFL can be irreversibly activated under pathologic conditions, leading to perpetual fibroblast activation. Sustained activation of the Twist1-Prrx1-TNC PFL reproduces fibrotic nodules similar to idiopathic pulmonary fibrosis in vivo and is implicated in fibrotic disease and cancer stroma. Considering that this PFL is specific to activated fibroblasts, Twist1-Prrx1-TNC PFL may be a fibroblast-specific therapeutic target to deprogram perpetually activated fibroblasts.

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Authors
Yeo, S.-Y., Lee, K.-W., Shin, D., An, S., Cho, K.-H., & Kim, S.-H.
Affiliations
  • Sungkyunkwan University (KR)
  • Korea Advanced Institute of Science and Technology (KR)
  • Samsung Medical Center (KR)
Corresponding author
  • Cho, Kwang-Hyun
  • Kim, Seok-Hyung
Venue
Nature Communications
Published
2018-08-01
Volume
9
Issue
1
Pages
3016-3016
ISSN
2041-1723 (ISSN-L)
OpenAlex
W2883191015
Cited by
115
References
57
Citations by year
2026: 11 · 2025: 8 · 2024: 18 · 2023: 16 · 2022: 17 · 2021: 21 · 2020: 18 · 2019: 5 · 2018: 1
FWCI
4.00
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Research Foundation (2015R1A2A1A15054021)
  • Ministry of Health, Welfare and Family Affairs | Korea National Institute of Health (HI14C2517)
  • National Research Foundation of Korea (2017R1A2A1A17069642, 2015M3A9A7067220, 2013M3A9A7046303)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
  • Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
Keywords
fibroblast activation, positive feedback loop, TWIST1, PRRX1, tenascin-C, bistability, cancer-associated fibroblasts, fibrosis, idiopathic pulmonary fibrosis, tumor stroma, wound healing, gene regulatory networks
MeSH terms
Cancer-Associated Fibroblasts, Animals, Cell Line, Feedback, Fibroblasts, Fibrosis, Humans, Mice, Inbred BALB C, Nuclear Proteins, Homeodomain Proteins, Tenascin, Systems Biology, Twist-Related Protein 1

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