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A positive feedback loop bi-stably activates fibroblasts

Author

Listed:
  • So-Young Yeo

    (Sungkyunkwan University)

  • Keun-Woo Lee

    (Sungkyunkwan University)

  • Dongkwan Shin

    (Korea Advanced Institute of Science and Technology (KAIST))

  • Sugyun An

    (Korea Advanced Institute of Science and Technology (KAIST))

  • Kwang-Hyun Cho

    (Korea Advanced Institute of Science and Technology (KAIST))

  • Seok-Hyung Kim

    (Sungkyunkwan University
    Sungkyunkwan University School of Medicine
    Sungkyunkwan University School of Medicine)

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.

Suggested Citation

  • So-Young Yeo & Keun-Woo Lee & Dongkwan Shin & Sugyun An & Kwang-Hyun Cho & Seok-Hyung Kim, 2018. "A positive feedback loop bi-stably activates fibroblasts," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05274-6
    DOI: 10.1038/s41467-018-05274-6
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    Cited by:

    1. Saeed, Mahdisoltani & Ramin, Golestanian, 2023. "Nonequilibrium phenomena in driven and active Coulomb field theories," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 631(C).
    2. Keyong Sun & Runda Xu & Fuhai Ma & Naixue Yang & Yang Li & Xiaofeng Sun & Peng Jin & Wenzhe Kang & Lemei Jia & Jianping Xiong & Haitao Hu & Yantao Tian & Xun Lan, 2022. "scRNA-seq of gastric tumor shows complex intercellular interaction with an alternative T cell exhaustion trajectory," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Sébastien Thériault & Zhonglin Li & Erik Abner & Jian’an Luan & Hasanga D. Manikpurage & Ursula Houessou & Pardis Zamani & Mewen Briend & Dominique K. Boudreau & Nathalie Gaudreault & Lily Frenette & , 2024. "Integrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. Keun-Woo Lee & So-Young Yeo & Jeong-Ryeol Gong & Ok-Jae Koo & Insuk Sohn & Woo Yong Lee & Hee Cheol Kim & Seong Hyeon Yun & Yong Beom Cho & Mi-Ae Choi & Sugyun An & Juhee Kim & Chang Ohk Sung & Kwang-, 2022. "PRRX1 is a master transcription factor of stromal fibroblasts for myofibroblastic lineage progression," Nature Communications, Nature, vol. 13(1), pages 1-23, December.

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