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EMBRYONIC STEM CELLS

Cardioinductive Network Guiding Stem Cell Differentiation Revealed by Proteomic Cartography of Tumor Necrosis Factor -Primed Endodermal Secretome

Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

Key Words. Embryonic stem cell • Cardiopoiesis • Endoderm • Secretome • Proteomics • Two-dimensional gel electrophoresis Multidimensional liquid chromatography-tandem mass spectrometry • Network biology • Systems biology

Correspondence: Andre Terzic, M.D., Ph.D., Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA. Telephone: 507-284-2747; Fax: 507-266-9936; e-mail: terzic.andre{at}mayo.edu

Received July 25, 2007; accepted for publication October 24, 2007.
First published online in STEM CELLS EXPRESS   November 8, 2008.



In the developing embryo, instructive guidance from the ventral endoderm secures cardiac program induction within the anterolateral mesoderm. Endoderm-guided cardiogenesis, however, has yet to be resolved at the proteome level. Here, through cardiopoietic priming of the endoderm with the reprogramming cytokine tumor necrosis factor (TNF), candidate effectors of embryonic stem cell cardiac differentiation were delineated by comparative proteomics. Differential two-dimensional gel electrophoretic mapping revealed that more than 75% of protein species increased >1.5-fold in the TNF-primed versus unprimed endodermal secretome. Protein spot identification by linear ion trap quadrupole (LTQ) tandem mass spectrometry (MS/MS) and validation by shotgun LTQ-Fourier transform MS/MS following multidimensional chromatography mapped 99 unique proteins from 153 spot assignments. A definitive set of 48 secretome proteins was deduced by iterative bioinformatic screening using algorithms for detection of canonical and noncanonical indices of secretion. Protein-protein interaction analysis, in conjunction with respective expression level changes, revealed a nonstochastic TNF-centric secretome network with a scale-free hierarchical architecture. Cardiovascular development was the primary developmental function of the resolved TNF-anchored network. Functional cooperativity of the derived cardioinductive network was validated through direct application of the TNF-primed secretome on embryonic stem cells, potentiating cardiac commitment and sarcomerogenesis. Conversely, inhibition of primary network hubs negated the procardiogenic effects of TNF priming. Thus, proteomic cartography establishes a systems biology framework for the endodermal secretome network guiding stem cell cardiopoiesis.

Disclosure of potential conflicts of interest is found at the end of this article.

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