A positive feedback loop bi-stably activates fibroblasts
Open accessAbstract
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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PRRX1 and TWIST1 were identified as key members of fibroblast transcriptional regulatory networks and are involved in a positive feedback loop that leads to fibroblast activation.
“They were both identified as key members of fibroblast transcriptional regulatory networks and involved in a positive feedback loop that leads to fibroblast activation16,17.”
From Integrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation (2024) · cites this paper as [17]
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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)
- PMC
- PMC6070563
- 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
- gold
- doi.org
- 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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