2. Academic Validation
  3. A positive mechanobiological feedback loop controls bistable switching of cardiac fibroblast phenotype

A positive mechanobiological feedback loop controls bistable switching of cardiac fibroblast phenotype

  • Cell Discov. 2022 Sep 6;8(1):84. doi: 10.1038/s41421-022-00427-w.
Lele Niu  # 1 2,  Bo Cheng  # 1 2,  Guoyou Huang 3,  Kai Nan 4,  Shuang Han 2 5,  Hui Ren 2 6,  Na Liu 7,  Yan Li 8,  Guy M Genin 1 2 9 10,  Feng Xu 11 12
Affiliations

Affiliations

  • 1 The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 2 Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 3 Department of Engineering Mechanics, School of Civil Engineering, Wuhan University, Wuhan, Hubei, China.
  • 4 Department of Orthopedics Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 5 Honghui Hospital, Xi'an, Shaanxi, China.
  • 6 Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 7 Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 8 Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 9 Department of Mechanical Engineering & Materials Science, Washington University in St. Louis, St. Louis, MO, USA.
  • 10 NSF Science and Technology Center for Engineering Mechanobiology, Washington University in St. Louis, St. Louis, MO, USA.
  • 11 The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China. [email protected].
  • 12 Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, Shaanxi, China. [email protected].
  • # Contributed equally.
PMID: 36068215 DOI: 10.1038/s41421-022-00427-w
Abstract

Cardiac fibrosis is associated with activation of cardiac fibroblasts (CFs), a pathological, phenotypic transition that is widely believed to be irreversible in the late stages of disease development. Sensing of a stiffened mechanical environment through regulation of integrin-based adhesion plaques and activation of the Piezo1 mechanosensitive ion channel is known to factor into this transition. Here, using integrated in vitro and in silico models, we discovered a mutually reinforcing, mechanical positive feedback loop between Integrin β1 and Piezo1 activation that forms a bistable switch. The bistable switch is initiated by perturbations in matrix elastic modulus that amplify to trigger downstream signaling involving Ca2+ and YAP that, recursively, leads fibroblasts to further stiffen their environment. By simultaneously interfering with the newly identified mechanical positive feedback loop and modulating matrix elastic modulus, we reversed markers of phenotypical transition of CF, suggesting new therapeutic targets for fibrotic disease.

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