Oncostatin M Is a Major Mediator of Cardiomyocyte Dedifferentiation and Remodeling

• Published in: Cell stem cell 2011-11, Vol.9 (5), p.420-432
• Main Authors: Kubin, Thomas, Pöling, Jochen, Kostin, Sawa, Gajawada, Praveen, Hein, Stefan, Rees, Wolfgang, Wietelmann, Astrid, Tanaka, Minoru, Lörchner, Holger, Schimanski, Silvia, Szibor, Marten, Warnecke, Henning, Braun, Thomas
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biomarkers - metabolism; Blotting, Western; Cardiomyopathy, Dilated - metabolism; Cardiomyopathy, Dilated - physiopathology; Cardiotonic Agents - metabolism; Cell Cycle - drug effects; Cell Dedifferentiation - drug effects; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; DNA - biosynthesis; Fluorescent Antibody Technique; Fundamental and applied biological sciences. Psychology; Gene Deletion; Gene Expression Regulation - drug effects; Heart Function Tests - drug effects; Humans; Mice; Mice, Transgenic; Molecular and cellular biology; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocardium - pathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Oncostatin M - metabolism; Oncostatin M - pharmacology; Oncostatin M Receptor beta Subunit - metabolism; Rats; Signal Transduction - drug effects; Signal Transduction - genetics; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - metabolism; Ventricular Remodeling - drug effects; Ventricular Remodeling - physiology
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2011.08.013

Cardiomyocyte remodeling, which includes partial dedifferentiation of cardiomyocytes, is a process that occurs during both acute and chronic disease processes. Here, we demonstrate that oncostatin M (OSM) is a major mediator of cardiomyocyte dedifferentiation and remodeling during acute myocardial infarction (MI) and in chronic dilated cardiomyopathy (DCM). Patients suffering from DCM show a strong and lasting increase of OSM expression and signaling. OSM treatment induces dedifferentiation of cardiomyocytes and upregulation of stem cell markers and improves cardiac function after MI. Conversely, inhibition of OSM signaling suppresses cardiomyocyte remodeling after MI and in a mouse model of DCM, resulting in deterioration of heart function after MI but improvement of cardiac performance in DCM. We postulate that dedifferentiation of cardiomyocytes initially protects stressed hearts but fails to support cardiac structure and function upon continued activation. Manipulation of OSM signaling provides a means to control the differentiation state of cardiomyocytes and cellular plasticity. ► Oncostatin M induces dedifferentiation of cardiomyocytes in vitro and in vivo via Oβ ► OSM induces progenitor cell markers in cardiomyocytes in vitro and in vivo ► OSM-mediated dedifferentiation protects the myocardium after cardiac infarction ► Extended dedifferentiation of cardiomyocytes by OSM impairs cardiac function