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2016 DEPARTMENT OF MEDICINE RESEARCH DAY Title of Poster: Cardiac fibroblasts adopt osteogenic cell fates and contribute to pathologic heart calcification Presenter: Shen Li Division: Department of Cardiology ☐ Faculty ☐ Fellow ☐ Resident ☒ Post-doc Research Fellow ☐ Graduate Student ☐ Medical Student ☐Other Principal Investigator/Mentor: Arjun Deb Co-Investigators: Indulekha C.L. Pillai, Shen Li, Milagros Romay, Larry Lam, Yan Lu, Jie Huang, Nathaniel Dillard, Marketa Zemanova, Liudmilla Rubbi, Yibin Wang, Jason Lee, Ming Xia, Owen Liang, Ya-Hong Xie, Matteo Pellegrini, Aldons J. Lusis Thematic Poster Category: Development, Morphogenesis, Cell Growth and Differentiation, Apoptosis, Stem Cell Biology, Carcinogenesis and Cancer Biology Abstract Mammalian tissues calcify with age and injury. Ectopic calcification of soft tissues is thought to be a dynamic cell mediated process analogous to bone formation in the skeletal system, in which bone forming cells are recruited to the affected tissue, deposit extracellular matrix and induce mineralization of the matrix. In the heart, calcification of heart muscle can lead to conduction system disturbances and is one of the most common pathologies underlying heart blocks. In this report, we investigate the identity of the cell and target mechanisms that contribute to pathologic heart muscle calcification. Using genetic fate map techniques, murine models of heart calcification and in vivo cell transplantation assays, we show that the cardiac fibroblast adopts an osteoblast cell-like fate and contributes directly to heart muscle calcification. ENPP1 an enzyme that generates pyrophosphate and promotes formation of phosphate and hydroxyapatite in the normal skeleton is induced in cardiac fibroblasts after injury. Inhibition of ENPP1 with small molecules significantly attenuated pathologic cardiac calcification and inhibitors of bone mineralization completely prevented ectopic cardiac calcification and led to better preservation of post injury cardiac function. Taken together, these findings highlight the plasticity of cardiac fibroblasts in contributing to pathologic tissue calcification and identify pharmacological targets for treating ectopic cardiac calcification.
