title: Cardiac Fibroblasts Adopt Osteogenic Fates and Can Be Targeted to Attenuate Pathological Heart Calcification.
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.
authors.affiliation: 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.
authors.forename: Indulekha C L
authors.initials: ICL
authors.lastname: Pillai
authors.affiliation: 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.
authors.forename: Shen
authors.initials: S
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Milagros
authors.initials: M
authors.lastname: Romay
authors.affiliation: 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.
authors.forename: Larry
authors.initials: L
authors.lastname: Lam
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Dillard
authors.affiliation: 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.
authors.forename: Marketa
authors.initials: M
authors.lastname: Zemanova
authors.affiliation: 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.
authors.forename: Liudmilla
authors.initials: L
authors.lastname: Rubbi
authors.affiliation: 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.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Jason
authors.initials: J
authors.lastname: Lee
authors.affiliation: Jonsson Comprehensive Cancer Center, UCLA, CA 90095, USA; Department of Materials Science & Engineering, School of Engineering, UCLA, CA 90095, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Xia
authors.affiliation: Jonsson Comprehensive Cancer Center, UCLA, CA 90095, USA; Department of Materials Science & Engineering, School of Engineering, UCLA, CA 90095, USA.
authors.forename: Owen
authors.initials: O
authors.lastname: Liang
authors.affiliation: Jonsson Comprehensive Cancer Center, UCLA, CA 90095, USA; Department of Materials Science & Engineering, School of Engineering, UCLA, CA 90095, USA.
authors.forename: Ya-Hong
authors.initials: YH
authors.lastname: Xie
authors.affiliation: 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.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: 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.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: 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.
authors.forename: Arjun
authors.initials: A
authors.lastname: Deb
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002113:Calcification, Physiologic; D002114:Calcinosis / Q000473:pathology* / Q000503:physiopathology; D009202:Cardiomyopathies / Q000473:pathology* / Q000503:physiopathology; D002454:Cell Differentiation; D019070:Cell Lineage; D002469:Cell Separation; D011756:Diphosphates / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D010012:Osteogenesis; D010710:Phosphates / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011755:Pyrophosphatases / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D011756:Diphosphates; D010710:Phosphates; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; C112923:Tcf21 protein, mouse; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1