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Nat. Commun., Published: 01 August 2018, 9, Article number: 3016 | https://doi.org/10.1038/s41467-018-05274-6
A positive feedback loop bi-stably activates fibroblasts
So-Young Yeo1, Keun-Woo Lee1, Dongkwan Shin2, Sugyun An2, Kwang-Hyun Cho2,* & Seok-Hyung Kim1,3,4,*
1Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul 06351, Republic of Korea. 2Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea. 3Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea. 4Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwona, Gyeonggi-do 16419, Republic of Korea. These authors contributed equally: So-Young Yeo, Keun-Woo Lee, Dongkwan Shin
*Correspondence to Kwang-Hyun Cho or Seok-Hyung Kim
1Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul 06351, Republic of Korea. 2Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea. 3Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea. 4Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwona, Gyeonggi-do 16419, Republic of Korea. These authors contributed equally: So-Young Yeo, Keun-Woo Lee, Dongkwan Shin
*Correspondence to Kwang-Hyun Cho or Seok-Hyung Kim
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.
논문정보
- Research article
- 2018년 08월 (BRIC 등록일 2018-08-22)
- 국내 연구진
- 의약학 > 종양의학
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