Jingyi Yu1,2,3,4,5,6, Marcus M Seldin1,2,7, Kai Fu3,4,5,6, Shen Li1,2,3,4,5,6, Larry Lam3,4,6, Ping Wang1,2,3,4,5,6, Yijie Wang1,2,3,4,5,6, Dian Huang8, Thang L Nguyen8, Bowen Wei9, Rajan P Kulkarni6,9, Dino Di Carlo6,8, Michael Teitell5,6,10, Matteo Pellegrini3,4,5,6, Aldons J Lusis1,2,7, Arjun Deb11,2,3,4,5,6. 1. From the Division of Cardiology, Department of Medicine (J.Y., M.M.S., S.L., P.W., Y.W., A.J.L., A.D.). 2. Cardiovascular Research Laboratory (J.Y., M.M.S., S.L., P.W., Y.W., A.J.L., A.D.). 3. Department of Molecular, Cell, and Developmental Biology (J.Y., K.F., S.L., L.L., P.W., Y.W., M.P., A.D.). 4. Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research (J.Y., K.F., S.L., L.L., P.W., Y.W., M.P., A.D.). 5. Molecular Biology Institute (J.Y., K.F., S.L., L.L., P.W., Y.W., M.T., M.P., A.D.). 6. Jonsson Comprehensive Cancer Center (J.Y., K.F., S.L., L.L., P.W., Y.W., R.P.K., D.D.C., M.T., M.P., A.D.). 7. Departments of Human Genetics and Microbiology, Immunology and Molecular Genetics (M.M.S., A.J.L.). 8. Department of Bioengineering (D.H., T.L.N., D.D.C.). 9. Division of Dermatology, Department of Medicine, David Geffen School of Medicine (B.W., R.P.K.). 10. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine (M.T.), University of California, Los Angeles. 11. From the Division of Cardiology, Department of Medicine (J.Y., M.M.S., S.L., P.W., Y.W., A.J.L., A.D.) adeb@mednet.ucla.edu.
Abstract
RATIONALE: Cardiac fibroblasts do not form a syncytium but reside in the interstitium between myocytes. This topological relationship between fibroblasts and myocytes is maintained throughout postnatal life until an acute myocardial injury occurs, when fibroblasts are recruited to, proliferate and aggregate in the region of myocyte necrosis. The accumulation or aggregation of fibroblasts in the area of injury thus represents a unique event in the life cycle of the fibroblast, but little is known about how changes in the topological arrangement of fibroblasts after cardiac injury affect fibroblast function. OBJECTIVE: The objective of the study was to investigate how changes in topological states of cardiac fibroblasts (such as after cardiac injury) affect cellular phenotype. METHODS AND RESULTS: Using 2 and 3-dimensional (2D versus 3D) culture conditions, we show that simple aggregation of cardiac fibroblasts is sufficient by itself to induce genome-wide changes in gene expression and chromatin remodeling. Remarkably, gene expression changes are reversible after the transition from a 3D back to 2D state demonstrating a topological regulation of cellular plasticity. Genes induced by fibroblast aggregation are strongly associated and predictive of adverse cardiac outcomes and remodeling in mouse models of cardiac hypertrophy and failure. Using solvent-based tissue clearing techniques to create optically transparent cardiac scar tissue, we show that fibroblasts in the region of dense scar tissue express markers that are induced by fibroblasts in the 3D conformation. Finally, using live cell interferometry, a quantitative phase microscopy technique to detect absolute changes in single cell biomass, we demonstrate that conditioned medium collected from fibroblasts in 3D conformation compared with that from a 2D state significantly increases cardiomyocyte cell hypertrophy. CONCLUSIONS: Taken together, these findings demonstrate that simple topological changes in cardiac fibroblast organization are sufficient to induce chromatin remodeling and global changes in gene expression with potential functional consequences for the healing heart.
RATIONALE: Cardiac fibroblasts do not form a syncytium but reside in the interstitium between myocytes. This topological relationship between fibroblasts and myocytes is maintained throughout postnatal life until an acute myocardial injury occurs, when fibroblasts are recruited to, proliferate and aggregate in the region of myocyte necrosis. The accumulation or aggregation of fibroblasts in the area of injury thus represents a unique event in the life cycle of the fibroblast, but little is known about how changes in the topological arrangement of fibroblasts after cardiac injury affect fibroblast function. OBJECTIVE: The objective of the study was to investigate how changes in topological states of cardiac fibroblasts (such as after cardiac injury) affect cellular phenotype. METHODS AND RESULTS: Using 2 and 3-dimensional (2D versus 3D) culture conditions, we show that simple aggregation of cardiac fibroblasts is sufficient by itself to induce genome-wide changes in gene expression and chromatin remodeling. Remarkably, gene expression changes are reversible after the transition from a 3D back to 2D state demonstrating a topological regulation of cellular plasticity. Genes induced by fibroblast aggregation are strongly associated and predictive of adverse cardiac outcomes and remodeling in mouse models of cardiac hypertrophy and failure. Using solvent-based tissue clearing techniques to create optically transparent cardiac scar tissue, we show that fibroblasts in the region of dense scar tissue express markers that are induced by fibroblasts in the 3D conformation. Finally, using live cell interferometry, a quantitative phase microscopy technique to detect absolute changes in single cell biomass, we demonstrate that conditioned medium collected from fibroblasts in 3D conformation compared with that from a 2D state significantly increases cardiomyocyte cell hypertrophy. CONCLUSIONS: Taken together, these findings demonstrate that simple topological changes in cardiac fibroblast organization are sufficient to induce chromatin remodeling and global changes in gene expression with potential functional consequences for the healing heart.
Authors: Evangelos P Daskalopoulos; Kevin C M Hermans; Ben J A Janssen; W Matthijs Blankesteijn Journal: Trends Cardiovasc Med Date: 2012-12-21 Impact factor: 6.677
Authors: Brian J Bennett; Charles R Farber; Luz Orozco; Hyun Min Kang; Anatole Ghazalpour; Nathan Siemers; Michael Neubauer; Isaac Neuhaus; Roumyana Yordanova; Bo Guan; Amy Truong; Wen-pin Yang; Aiqing He; Paul Kayne; Peter Gargalovic; Todd Kirchgessner; Calvin Pan; Lawrence W Castellani; Emrah Kostem; Nicholas Furlotte; Thomas A Drake; Eleazar Eskin; Aldons J Lusis Journal: Genome Res Date: 2010-01-06 Impact factor: 9.043
Authors: Megan M Monsanto; Bingyan J Wang; Zach R Ehrenberg; Oscar Echeagaray; Kevin S White; Roberto Alvarez; Kristina Fisher; Sharon Sengphanith; Alvin Muliono; Natalie A Gude; Mark A Sussman Journal: Nat Commun Date: 2020-08-07 Impact factor: 14.919