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Bad Rothenfelde, Germany

Szibor M.,Max Planck Institute for Heart and Lung Research | Szibor M.,University of Helsinki | Poling J.,Max Planck Institute for Heart and Lung Research | Warnecke H.,Schuchtermann Clinic | And 2 more authors.
Cellular and Molecular Life Sciences | Year: 2014

Cardiomyocytes continuously generate the contractile force to circulate blood through the body. Imbalances in contractile performance or energy supply cause adaptive responses of the heart resulting in adverse rearrangement of regular structures, which in turn might lead to heart failure. At the cellular level, cardiomyocyte remodeling includes (1) restructuring of the contractile apparatus; (2) rearrangement of the cytoskeleton; and (3) changes in energy metabolism. Dedifferentiation represents a key feature of cardiomyocyte remodeling. It is characterized by reciprocal changes in the expression pattern of "mature" and "immature" cardiomyocyte-specific genes. Dedifferentiation may enable cardiomyocytes to cope with hypoxic stress by disassembly of the energy demanding contractile machinery and by reduction of the cellular energy demand. Dedifferentiation during myocardial repair might provide cardiomyocytes with additional plasticity, enabling survival under hypoxic conditions and increasing the propensity to enter the cell cycle. Although dedifferentiation of cardiomyocytes has been described during tissue regeneration in zebrafish and newts, little is known about corresponding mechanisms and regulatory circuits in mammals. The recent finding that the cytokine oncostatin M (OSM) is pivotal for cardiomyocyte dedifferentiation and exerts strong protective effects during myocardial infarction highlights the role of cytokines as potent stimulators of cardiac remodeling. Here, we summarize the current knowledge about transient dedifferentiation of cardiomyocytes in the context of myocardial remodeling, and propose a model for the role of OSM in this process. © 2013 Springer Basel.

Poling J.,Max Planck Institute for Heart and Lung Research | Gajawada P.,Max Planck Institute for Heart and Lung Research | Lorchner H.,Max Planck Institute for Heart and Lung Research | Polyakova V.,Max Planck Institute for Heart and Lung Research | And 5 more authors.
Cell Cycle | Year: 2012

Dedifferentiation is a common phenomenon among plants but has only rarely been found in vertebrates, where it is mostly associated with regenerative responses such as formation of blastemae in amphibians to initiate replacement of lost body parts. Relatively little attention has been paid to dedifferentiation processes in mammals, although a decline of differentiated functions and acquisition of immature, "embryonic" properties is seen in various disease processes. Dedifferentiation of parenchymal cells in mammals might serve multiple purposes, including (1) facilitation of tissue regeneration by generation of progenitor-like cells and (2) protection of cells from hypoxia by reduction of ATP consumption due to changes in energy metabolism and/or inactivation of energy-intensive "specialized"functions. We recently found that an inflammatory cytokine of the interleukin 6 family oncostatin M (OSM) initiates dedifferentiation of cardiomyocytes both in vitro and in vivo. Interestingly, activation of the OSM signaling pathway protects the heart from acute myocardial ischemia but has a negative impact when continuously activated, thereby promoting dilative cardiomyopathy. The strong presence of the OSM receptor on cardiomyocytes and the unique features of the OSM signaling circuit suggest a major role of OSM for cardiac protection and repair. We propose that continuous activation or malfunctions of the cellular dedifferentiation machinery might contribute to different disease conditions. © 2012 Landes Bioscience.

Hou Y.,Max Planck Institute for Heart and Lung Research | Adrian-Segarra J.M.,Max Planck Institute for Heart and Lung Research | Richter M.,Kerckhoff Clinic | Kubin N.,Max Planck Institute for Heart and Lung Research | And 10 more authors.
BioMed Research International | Year: 2015

It is now accepted that heart failure (HF) is a complex multifunctional disease rather than simply a hemodynamic dysfunction. Despite its complexity, stressed cardiomyocytes often follow conserved patterns of structural remodelling in order to adapt, survive, and regenerate. When cardiac adaptations cannot cope with mechanical, ischemic, and metabolic loads efficiently or become chronically activated, as, for example, after infection, then the ongoing structural remodelling and dedifferentiation often lead to compromised pump function and patient death. It is, therefore, of major importance to understand key events in the progression from a compensatory left ventricular (LV) systolic dysfunction to a decompensatory LV systolic dysfunction and HF. To achieve this, various animal models in combination with an "omics" toolbox can be used. These approaches will ultimately lead to the identification of an arsenal of biomarkers and therapeutic targets which have the potential to shape the medicine of the future. Copyright © 2015 Yunlong Hou et al.

Polyakova V.,Kerckhoff Clinic | Polyakova V.,Max Planck Institute for Heart and Lung Research | Richter M.,Kerckhoff Clinic | Ganceva N.,Kerckoff Clinic | And 9 more authors.
IJC Heart and Vessels | Year: 2014

Objectives: We used immuhistochemistry and Western blot to study fibrillar and non-fibrillar collagens, collagen metabolism, matricellular proteins and regulatory factors of the ECM remodeling in left ventricular (LV) septum biopsies from 3 groups of patients with aortic valve stenosis (AS): (AS-1,n = 9): ejection fraction (EF). > 50%; AS-2,(n = 12): EF 30%-50%; AS-3,(n = 9): EF. < 30%). Samples from 8 hearts with normal LV function served as controls. Results: In comparison with controls, fibrillar collagens I and III were progressively upregulated from compensated (AS-1) toward decompensated hypertrophy (AS-3). The collagenIII/collagen I ratio decreased 2-fold in the AS-2 and AS-3 groups as compared with AS-1 and controls. Non-fibrillar collagen IV was upregulated only in AS-3 patients, whereas collagen VI progressively increased from AS-1 to AS-3 group. Collagen synthesis in AS-3 was shifted to collagen I, while the maturation/degradation level was shifted to collagen III. RECK was downregulated only in AS-3 patients. Matricellular proteins tenascin and osteopontin were increased in all AS patients. However, thrombospondin 1, 4 and CTGF were increased only in AS-3. Only AS-3 patients were characterized by increased levels of TGFβ1 and downregulation of TGFβ3, TGFβ-activated kinase1 and Smad7. In contrast, Smad3 gradually increased from AS-1 toward AS-3. Similar trend of changes was observed for TNFα-R1 and TNFα-R2, whereas TNFα was diminished only in AS-2 and AS-3. Conclusions: Distinct changes in fibrillar collagen turnover, non-fibrillar collagens, matricellular proteins and the key regulatory profibrotic and anti-fibrotic factors of the myocardial ECM remodeling are involved in the transition from compensated to decompensated LV hypertrophy and HF in human patients with AS. © 2014 The Authors. Published by Elsevier Ireland Ltd.

Lorchner H.,Max Planck Institute for Heart and Lung Research | Poling J.,Max Planck Institute for Heart and Lung Research | Gajawada P.,Max Planck Institute for Heart and Lung Research | Hou Y.,Max Planck Institute for Heart and Lung Research | And 9 more authors.
Nature Medicine | Year: 2015

Cardiac healing after myocardial ischemia depends on the recruitment and local expansion of myeloid cells, particularly macrophages. Here we identify Reg3β as an essential regulator of macrophage trafficking to the damaged heart. Using mass spectrometry-based secretome analysis, we found that dedifferentiating cardiomyocytes release Reg3β in response to the cytokine OSM, which signals through Jak1 and Stat3. Loss of Reg3β led to a large decrease in the number of macrophages in the ischemic heart, accompanied by increased ventricular dilatation and insufficient removal of neutrophils. This defect in neutrophil removal in turn caused enhanced matrix degradation, delayed collagen deposition and increased susceptibility to cardiac rupture. Our data indicate that OSM, acting through distinct intracellular pathways, regulates both cardiomyocyte dedifferentiation and cardiomyocyte-dependent regulation of macrophage trafficking. Release of OSM from infiltrating neutrophils and macrophages initiates a positive feedback loop in which OSM-induced production of Reg3β in cardiomyocytes attracts additional OSM-secreting macrophages. The activity of the feedback loop controls the degree of macrophage accumulation in the heart, which is instrumental in myocardial healing.

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