Influence of extracellular matrix components on cardiac progenitor cell-mediated myocardial regeneration
Final Report Abstract
In the western world heart failure is the leading cause of mortality and current therapeutic concepts only serve to delay the progression of the disease. Regenerative medicine opens up novel therapeutic modalities. Especially, the discovery of resident multipotent cardiovascular progenitor cells (CPCs) in mammalian postnatal (adult) heart raises hope for autologous cell therapy improving cardiac function and clinical outcome. Within the myocardium the extracellular matrix (ECM) is an integral participant in maintenance of cardiac function that regulates cellular components. ECM proteins are determinants for influencing cell-cell interaction and providing pivotal signals regarding cell fate. Fibronectin (Fn), an ECM protein, is present at low levels in healthy adult heart tissue and highly up-regulated early in development as well as in response to pathological injury. Spatiotemporal expression of Fn correlates with the presence of cardiac progenitor cells (CPC) in wounded myocardium after infarction, disappearing again within 1 month. The receptor for Fn on the cell surface is a5β1 integrin that promotes activation of cardioprotective kinases including focal adhesion kinase (FAK) and Pim-1 in CPCs, leading to proliferation and inhibition of apoptosis. The causal contribution of Fn in regeneration and wound healing after Ml is to be confirmed by ongoing studies of a conditional Fn knock-out mouse, that has been successfully created. To establish relevance of these findings for human pathophysiology, key in vitro experiments were repeated with human CPCs. Understanding of the molecular mechanism of the described Fn-a5β1-Pim-1 pathway in CPCs allows deduction of novel treatment options for heart failure with regenerative medicine.
Publications
-
An MEK-cofilin signalling module controls migration of human T cells in 3D but not 2D environments. EMBO J. 2010 Sep 1;29{17):2915-29
Klemke M, Kramer E, Konstandin MH, Wabnitz GH, Samstag Y
-
Mitochondrial translocation of oxidized cofilin induces caspase-independent necrolic-like programmed cell death of T cells. Cell Death Dis. 2010 Jul 22;1:e58
Wabnitz GH, Goursot C, Jahraus B, Kirchgessner H, Hellwig A, Klemke M, Konstandin MH, Samstag Y
-
Cardiac progenitor cell commitment is inhibited by nuclear Akt expression. Circ Res. 2011 Apr 15;108(8):960-70
Fischer KM, Din S, Gude N, Konstandin MH, Wu W, Quijada P, Sussman MA
-
Impact of troponin I-autoantibodies in chronic dilated and ischemic cardiomyopathy. Basic Res Cardiol. 2011 Jan;106(1):25-35
Doesch AO, Mueller S, Nelles M, Konstandin M, Celik S, Frankenstein L, Goeser S, Kaya Z, Koch A, Zugck C, Katus HA
-
Mitochondrial translocation of Nur77 mediates cardiomyocyte apoptosis. Eur Heart J. 2011 Sep;32(17):2179-88
Cheng Z, Völkers M, Din S, Avitabile D, Khan M, Gude N, Mohsin S, Bo T, Truffa S, Alvarez R, Mason M, Fischer KM, Konstandin MH, Zhang XK, Heller Brown J, Sussman MA
-
Myocardial AKT: the omnipresent nexus. Physiol Rev. 2011 Jul;91(3):1023-70
Sussman MA, Völkers M, Fischer K, Bailey B, Cottage CT, Din S, Gude N, Avitabile D, Alvarez R, Sundararaman B, Quijada P, Mason M, Konstandin MH, Malhowski A, Cheng Z, Khan M, McGregor M
-
Nucleolar stress is an early response to myocardial damage involving nucleolar proteins nucleostemin and nucleophosmin. Proc Natl Acad Sei U S A . 2011 Apr 12;108(15):6145-50
Avitabile D, Bailey B, Cottage CT, Sundararaman B, Joyo A, McGregor M, Gude N, Truffa S, Zarrabi A, Konstandin M, Khan M, Mohsin S, Völkers M, Toko H, Mason M, Cheng Z, Din S, Alvarez R Jr, Fischer K, Sussman MA
-
Pim-1 kinase inhibits pathological injury by promoting cardioprotective signaling. J Mol Cell Cardiol. 2011 Oct;51(4):554-8. Epub 2011 Jan 19
Fischer KM, Cottage CT, Konstandin MH, Völkers M, Khan M, Sussman MA
-
Pronounced coronary artery calcification: casual finding in transthoracic echocardiography. Int J Cardiol. 2011 Jul 15;150(2):e53-4
Konstandin MH, Hardt SE, Katus HA, Mereles D
-
Severe right ventricular outflow tract obstruction caused by non-hodgkin lymphoma: complete regression after one course of bendamustine/rituximab therapy. J Am Soc Echocardiogr. 2011 Jul;24(7):818.e1-4
Konstandin MH, Korosoglou G, Hosch W, Hardt SE, Katus HA, Mereles D
