The heart is unable to regenerate heart muscle after a heart attack and lost cardiac muscle is replaced by scar tissue. Scar tissue does not contribute to cardiac contractile force and the remaining viable cardiac muscle is thus subject to a greater hemodynamic burden. Over time, the heart muscle eventually fails leading to the development of heart failure and 500,000 patients are diagnosed annually in the United States with heart failure. Thus the inability of the heart to regenerate cardiac muscle, coupled with a predominant fibrotic injury response remain major fundamental obstacles to treating heart disease.
Our laboratory studies the interface of cardiac fibroblasts (scar forming cells) and cardiac progenitors in determining how a cross talk between these cells regulates cardiac repair. We use murine models of cardiac injury and use a variety of fate mapping and conditional knockout strategies to alter specific genes at specific time points after injury to investigate our questions. We study the Wnt signaling pathway, a family of 19 closely related proteins that play key roles in organogenesis, wound healing and cancer. We have recently demonstrated that Wnt1, a Wnt known to play important roles in the development of the central nervous system plays an important role in regulating a fibrotic injury response in the heart. Using transgenic and conditional knock out strategies, we aim to alter the fibrotic repair response of the heart to enable regeneration.
Epicardium and mechanisms of EMT
The second area of investigation in our laboratory is to understand the role of cardiac cell plasticity and how plasticity can be modulated to affect wound healing in the adult heart. In this respect, we have recently shown that scar forming cells in the heart exhibit plasticity after cardiac injury and such plasticity can be modulated to affect the wound healing response (Nature 2014; 585-590). We study molecule mechanisms of such plasticity and aim to modulate the scar response by coaxing scar forming cells to adopt alternative cell fates. Another example of a plastic cardiac cell is the epicardial cell. The epicardium is a single layer of epithelial cells, that surrounds the heart. Although the epicardium is critically important for cardiac development, little is known about the function of the epicardium in the adult heart. We have recently demonstrated that the epicardium undergoes epithelial-mesenchymal-transition in a Wnt dependent manner after cardiac injury and generates cardiac fibroblasts that reside in the subepicardial space and contribute to cardiac fibrosis. The molecular regulation of epicardial EMT, identification of precursors in the epicardium that give rise to cardiac fibroblasts and its role in wound healing form another major focus in our laboratory.
Calcification of the heart is a predominant phenotype of the aging heart and pathologic calcification predisposes to cardiac disease. For instance, calcification of the conduction system in humans causes slowing of conduction and heart blocks, while calcification of the valves leads to stiffening of the valve leaflets, and obstruction or regurgitation of blood across the valves secondary to defective coaptation of valve leaflets. The origins of the cells contributing to cardiac calcification and mechanisms regulating calcium deposition remain ill understood. Using human heart valves (obtained during surgical replacement of calcific heart valves), we isolate and study progenitor populations that can contribute to cardiac calcification. We also have murine models of calcification that we use to obtain fate maps about potential progenitor populations contributing to cardiac calcification and study mechanisms driving progenitors to adopt an osteoblast (calcium forming cell) fate. This project allows the interrogation of mechanisms in both murine models and human tissue.
Lluri Gentian, Renella Pierangelo, Finn J Paul, Vorobiof Gabriel, Aboulhosn Jamil, Deb Arjun, " Prognostic Significance of Left Ventricular Fibrosis in Patients With Congenital Bicuspid Aortic Valve", The American journal of Cardiology (2017). [link]
Monaghan, M. G., Holeiter, M., Brauchle, E., Layland, S. L., Lu, Y., Deb, A.*, Abhay, P., All, N., KatJa, S., Schenke-Layland, K., "Exogenous miR-29B Delivery Through a Hyaluronan-Based Injectable System Yields Functional Maintenance of the Infarcted Myocardium", Tissue Engineering Part A (2017). [link]
Seldin, M. M., Kim, E. D., Romay, M. C., Li, S., Rau, C. D., Wang, J. J., Krishnan, K.C., Wang, Y., Deb, A.*, Lusis, A. J., American Journal of Physiology - Heart and Circulatory Physiology 312 (4): H728-H741 (2017). [link]
Murray IR, Baily J, Chen WCW, Dar A, Gonzalez ZN, Jensen AR, Petrigliano FR, Deb A, Henderson NC, "Skeletal and Cardiac Muscle Pericytes: Functions and Therapeutic Potential", Pharmacology and Theraeutics 171: 65-74 (2017). [link]
Pillai I, Li S, Romay M, Lam L Lu Y, Jie Huang, Dillard N, Zemanova M, Rubbi L Wang Y, Lee J, Xia M, Pellegrini M, Lusis A, Deb A, "Cardiac fibroblasts adopt osteogenic cell fates and can be targeted to attenuate pathological heart calcification", Cell Stem Cell 20 (2): 218-232 (2017). [link]
Wang Z, Zhang X, Ji Y, Zhang P, Deng , Gong J, Ren S, Wang X, Chen I, Wang H, Gao C, Yoota T, Ang Y, Li S, Cass A, Vondriska V, Li G, Deb A, Srivastava D, Yang H, Xiao X, i H, Wang Y, "A Long non-coding RNA defines an epigenetic checkpoint for cardiac hypertrophy", Nature Medicine 22 (10): 1131-1139 (2016). [link]
Brumm A, Nunez S, Doroudchi M, Kawaguchi R, Duan J, Pellegrini M, Lam L, Carmichael T, Deb A, Hinman J, "Astrocytes can adopt endothelial cell fates in a p53 dependent manner", Molecular Neurobiology (2016). [link]
Deb A, Wang Y, "Hypertrophic preconditioning: short-term tricks for long-term gain", Circulation 131 (17): 1468-1470 (2015). [link]
Arjun Deb, Yibin Wang, "Hypertrophic preconditioning: Short term tricks for long term gain", Circulation (2015). [link]
Eric Ubil, Jinzhu Duan,Indulekha C. L. Pillai, Manuel Rosa-Garrido, Yong Wu, Francesca Bargiacchi, Yan Lu, Seta Stanbouly, Jie Huang, Mauricio Rojas, Thomas M. Vondriska, Enrico Stefani & Arjun Deb, ". Mesenchymal-endothelial transition contributes to cardiac neovascularization", Nature 514 (7524): 585-590 (2014). [link]
Arjun Deba, Eric Ubil, "Cardiac Fibroblast in Development and Wound healing", Journal of Molecular and Cellular Cardiology 70: 47-55 (2014). [link]
Arjun Deb, "Cell-Cell Interaction via the Wnt/β-catenin pathway after cardiac injury", Cardiovasc Res 102 (2): 214-223 (2014). [link]
JinZhu Duan, Yueh Lee, Corey Jania, Jucheng Gong, Mauricio Rojas, Laurel Burk, Monte Willis, Jonathon Homeister, Stephen Tilley, Janet Rubin, Arjun Deb, "Rib fractures and death from rapid osteoclastogenesis is rescued by corticosteroids", PLoS ONE 8 (2): (2013). [link]
Jinzhu Duan, Costin Gherghe, Dianxin Liu, Eric Hamlett, Luxman Srikantha, Laurel Rodgers, Jenna N Regan, Mauricio Rojas, Monte Willis, Andrew Leask, Mark Majesky, Arjun Deb, "Wnt1/β-catenin injury response activates the epicardium and cardiac fibroblasts and is critical for cardiac repair", The EMBO Journal 31 (2): 429-442 (2012). [link]
Costin M. Gherghe, Jinzhu Duan, Jucheng Gong, Mauricio Rojas, Nancy Klauber-Demore, Mark Majesky and Arjun Deb, "Wnt1 is a pro-angiogenic molecule, enhances human endothelial progenitor function and increases blood flow to ischemic limbs in a HGF dependent manner", The FASEB Journal 25 (6): 1836-1843 (2011). [link]