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Nat Cell Biol. 2019 Mar;21(3):348-358. doi: 10.1038/s41556-019-0272-y. Epub 2019 Feb 11.

MicroRNA-dependent regulation of biomechanical genes establishes tissue stiffness homeostasis.

Author information

1
Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiology, Yale University School of Medicine, New Haven, CT, USA.
2
Laboratoire de Physiologie et Pharmacologie, Faculty of Medicine, Université Libre De Bruxelles, Brussels, Belgium.
3
Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK.
4
Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
5
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
6
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
7
Department of Computer Science, Yale University, New Haven, CT, USA.
8
Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiology, Yale University School of Medicine, New Haven, CT, USA. martin.schwartz@yale.edu.
9
Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK. martin.schwartz@yale.edu.
10
Departments of Cell Biology and Biomedical Engineering, Yale University, New Haven, CT, USA. martin.schwartz@yale.edu.
11
Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiology, Yale University School of Medicine, New Haven, CT, USA. stefania.nicoli@yale.edu.
12
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. stefania.nicoli@yale.edu.
13
Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA. stefania.nicoli@yale.edu.

Abstract

Vertebrate tissues exhibit mechanical homeostasis, showing stable stiffness and tension over time and recovery after changes in mechanical stress. However, the regulatory pathways that mediate these effects are unknown. A comprehensive identification of Argonaute 2-associated microRNAs and mRNAs in endothelial cells identified a network of 122 microRNA families that target 73 mRNAs encoding cytoskeletal, contractile, adhesive and extracellular matrix (CAM) proteins. The level of these microRNAs increased in cells plated on stiff versus soft substrates, consistent with homeostasis, and suppressed targets via microRNA recognition elements within the 3' untranslated regions of CAM mRNAs. Inhibition of DROSHA or Argonaute 2, or disruption of microRNA recognition elements within individual target mRNAs, such as connective tissue growth factor, induced hyper-adhesive, hyper-contractile phenotypes in endothelial and fibroblast cells in vitro, and increased tissue stiffness, contractility and extracellular matrix deposition in the zebrafish fin fold in vivo. Thus, a network of microRNAs buffers CAM expression to mediate tissue mechanical homeostasis.

PMID:
30742093
PMCID:
PMC6528464
DOI:
10.1038/s41556-019-0272-y
[Indexed for MEDLINE]
Free PMC Article

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