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First published online November 8, 2007
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Submitted on July 25, 2007
Accepted on October 24, 2007

EMBRYONIC STEM CELLS

Cardioinductive Network Guiding Stem Cell Differentiation Revealed by Proteomic Cartography of TNF{alpha}-primed Endodermal Secretome

D. Kent Arrell 1, Nicolas J. Niederländer 1, Randolph S. Faustino 1, Atta Behfar 1, Andre Terzic 1*

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

* To whom correspondence should be addressed. E-mail: terzic.andre{at}mayo.edu.


  Abstract

In the developing embryo, instructive guidance from the ventral endoderm secures cardiac program induction within the antero-lateral mesoderm. Endoderm-guided cardiogenesis, however, has yet to be resolved at the proteome level. Here, through cardiogenic priming of the endoderm with the reprogramming cytokine TNF{alpha}, candidate effectors of embryonic stem cell cardiac differentiation were delineated by comparative proteomics. Differential two-dimensional gel electrophoretic mapping revealed that over 75% of protein species increased >1.5-fold in the TNF{alpha}-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 non-canonical indices of secretion. Protein-protein interaction analysis, in conjunction with respective expression level changes, revealed a non-stochastic TNF{alpha}-centric secretome network with a scale-free hierarchical architecture. Cardiovascular development was the primary developmental function of the resolved TNF{alpha}-anchored network. Functional cooperativity of the derived cardioinductive network was validated through direct application of the TNF{alpha}-primed secretome on embryonic stem cells, potentiating cardiac commitment and sarcomerogenesis. Conversely, inhibition of primary network hubs negated the pro-cardiogenic effects of TNF{alpha} priming. Thus, proteomic cartography establishes a systems biology framework for the endodermal secretome network guiding stem cell cardiac differentiation.

Key Words. embryonic stem cell, cardiopoiesis, endoderm, secretome, proteomics, 2-D gel electrophoresis, multidimensional LC-MS/MS, network biology, systems biology




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