Regulators of cardiac fibroblast cell state |
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| Institution: | 1. Department of Bioengineering, University of Washington, Seattle, WA 98105, United States;2. Department of Pathology, University of Washington, 850 Republican, #343, Seattle, WA 98109, United States;3. Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, WA 98109, United States;4. Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, United States;1. Division of Cardiology, University of Washington School of Medicine, Seattle, WA, USA;2. Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA;3. Department of Bioengineering, University of Washington, Seattle, WA, USA;1. Department of Pediatrics, University of Cincinnati, Cincinnati Children''s Hospital Medical Center, Cincinnati, OH 45229, USA;2. Howard Hughes Medical Institute, Cincinnati, OH 45229, USA;1. Division of Cardiology, Department of Medicine, Cardiovascular Research Laboratory, David Geffen School of Medicine at University of California, Los Angeles, USA;2. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine at University of California, Los Angeles, USA;3. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles, USA;4. Molecular Biology Institute, David Geffen School of Medicine at University of California, Los Angeles, USA;5. Program in Molecular Cellular & Integrative Physiology, David Geffen School of Medicine at University of California, Los Angeles, USA;6. Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill. |
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| Abstract: | Fibroblasts are the primary regulator of cardiac extracellular matrix (ECM). In response to disease stimuli cardiac fibroblasts undergo cell state transitions to a myofibroblast phenotype, which underlies the fibrotic response in the heart and other organs. Identifying regulators of fibroblast state transitions would inform which pathways could be therapeutically modulated to tactically control maladaptive extracellular matrix remodeling. Indeed, a deeper understanding of fibroblast cell state and plasticity is necessary for controlling its fate for therapeutic benefit. p38 mitogen activated protein kinase (MAPK), which is part of the noncanonical transforming growth factor β (TGFβ) pathway, is a central regulator of fibroblast to myofibroblast cell state transitions that is activated by chemical and mechanical stress signals. Fibroblast intrinsic signaling, local and global cardiac mechanics, and multicellular interactions individually and synergistically impact these state transitions and hence the ECM, which will be reviewed here in the context of cardiac fibrosis. |
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