Transplantation of pluripotent stem cells has proven beneficial in
heart failure, yet the proteomic landscape underlying repair remains largely uncharacterized. In a genetic model of
dilated cardiomyopathy elicited by pressure overload in the KCNJ11 (
potassium inwardly rectifying channel, subfamily J, member 11) null mutant,
proteome-wide profiles were here resolved by means of a systems approach prior to and following disease manifestation in the absence or presence of embryonic stem cell treatment. Comparative two-dimensional gel electrophoresis revealed a unique cardiomyopathic
proteome in the absence of
therapy, remodeled in response to stem cell treatment. Specifically, linear ion trap quadrupole-Orbitrap mass spectrometry determined the identities of 93 and 109 differentially expressed
proteins from treated and untreated cardiomyopathic hearts, respectively. Mapped
protein-
protein relationships and corresponding neighborhoods incorporated the stem cell-dependent subproteome into a nonstochastic network with divergent composition from the stem cell-independent counterpart. Stem cell intervention produced a distinct
proteome signature across a spectrum of biological processes ranging from energetic metabolism,
oxidoreductases, and stress-related chaperones to processes supporting
protein synthesis/degradation, signaling, and transport regulation, cell structure and scaffolding. In the absence of treatment, bioinformatic interrogation of the disease-only
proteome network prioritized adverse cardiac outcomes, ablated or ameliorated following
stem cell transplantation. Functional and structural measurements validated improved myocardial contractile performance, reduced ventricular size and decreased cardiac damage in the treated cohort. Unbiased systems assessment unmasked "cardiovascular development" as a prioritized
biological function in stem cell-reconstructed cardiomyopathic hearts. Thus, embryonic stem cell treatment transformed the cardiomyopathic
proteome to demote disease-associated adverse effects and sustain a procardiogenic developmental response, supplying a regenerative substrate for
heart failure repair.