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Cell Stem Cell. 2017 Feb 2;20(2):218-232.e5. doi: 10.1016/j.stem.2016.10.005. Epub 2016 Nov 17.

Cardiac Fibroblasts Adopt Osteogenic Fates and Can Be Targeted to Attenuate Pathological Heart Calcification.

Author information

1
Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), CA 90095, USA; Cardiovascular Research Laboratory, David Geffen School of Medicine, UCLA, CA 90095, USA; Department of Molecular, Cell and Developmental Biology, School of Letters and Sciences, UCLA, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, CA 90095, USA; Molecular Biology Institute, UCLA, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, CA 90095, USA.
2
Cardiovascular Research Laboratory, David Geffen School of Medicine, UCLA, CA 90095, USA; Departments of Human Genetics & Microbiology, Immunology, and Molecular Genetics, UCLA, CA 90095, USA.
3
Department of Molecular, Cell and Developmental Biology, School of Letters and Sciences, UCLA, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, CA 90095, USA; Molecular Biology Institute, UCLA, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, CA 90095, USA.
4
Cardiovascular Research Laboratory, David Geffen School of Medicine, UCLA, CA 90095, USA; Department of Anesthesiology, UCLA, CA 90095, USA; Department of Physiology, UCLA, CA 90095, USA.
5
Jonsson Comprehensive Cancer Center, UCLA, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine and Crump Institute for Molecular Imaging, UCLA, CA 90095, USA.
6
Jonsson Comprehensive Cancer Center, UCLA, CA 90095, USA; Department of Materials Science & Engineering, School of Engineering, UCLA, CA 90095, USA.
7
Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), CA 90095, USA; Cardiovascular Research Laboratory, David Geffen School of Medicine, UCLA, CA 90095, USA; Departments of Human Genetics & Microbiology, Immunology, and Molecular Genetics, UCLA, CA 90095, USA.
8
Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), CA 90095, USA; Cardiovascular Research Laboratory, David Geffen School of Medicine, UCLA, CA 90095, USA; Department of Molecular, Cell and Developmental Biology, School of Letters and Sciences, UCLA, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, CA 90095, USA; Molecular Biology Institute, UCLA, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, CA 90095, USA. Electronic address: adeb@mednet.ucla.edu.

Abstract

Mammalian tissues calcify with age and injury. Analogous to bone formation, osteogenic cells are thought to be recruited to the affected tissue and induce mineralization. In the heart, calcification of cardiac muscle leads to conduction system disturbances and is one of the most common pathologies underlying heart blocks. However the cell identity and mechanisms contributing to pathological heart muscle calcification remain unknown. Using lineage tracing, murine models of heart calcification and in vivo transplantation assays, we show that cardiac fibroblasts (CFs) adopt an osteoblast cell-like fate and contribute directly to heart muscle calcification. Small-molecule inhibition of ENPP1, an enzyme that is induced upon injury and regulates bone mineralization, significantly attenuated cardiac calcification. Inhibitors of bone mineralization completely prevented ectopic cardiac calcification and improved post injury heart function. Taken together, these findings highlight the plasticity of fibroblasts in contributing to ectopic calcification and identify pharmacological targets for therapeutic development.

PMID:
27867037
PMCID:
PMC5291784
DOI:
10.1016/j.stem.2016.10.005
[Indexed for MEDLINE]
Free PMC Article

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