Cardiogenic induction of pluripotent stem cells streamlined through a conserved SDF-1/VEGF/BMP2 integrated network.
BACKGROUND
Pluripotent stem cells produce tissue-specific lineages through programmed acquisition of sequential gene expression patterns that function as a blueprint for organ formation. As embryonic stem cells respond concomitantly to diverse signaling pathways during differentiation, extraction of a pro-cardiogenic network would offer a roadmap to streamline cardiac progenitor output.


RESULTS
To resolve gene ontology priorities within precursor transcriptomes, cardiogenic subpopulations were here generated according to either growth factor guidance or stage-specific biomarker sorting. Innate expression profiles were independently delineated through unbiased systems biology mapping, and cross-referenced to filter transcriptional noise unmasking a conserved progenitor motif (55 up- and 233 down-regulated genes). The streamlined pool of 288 genes organized into a core biological network that prioritized the "Cardiovascular Development" function. Recursive in silico deconvolution of the cardiogenic neighborhood and associated canonical signaling pathways identified a combination of integrated axes, CXCR4/SDF-1, Flk-1/VEGF and BMP2r/BMP2, predicted to synchronize cardiac specification. In vitro targeting of the resolved triad in embryoid bodies accelerated expression of Nkx2.5, Mef2C and cardiac-MHC, enhanced beating activity, and augmented cardiogenic yield.


CONCLUSIONS
Transcriptome-wide dissection of a conserved progenitor profile thus revealed functional highways that coordinate cardiogenic maturation from a pluripotent ground state. Validating the bioinformatics algorithm established a strategy to rationally modulate cell fate, and optimize stem cell-derived cardiogenesis.
Chiriac
Anca
A
Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
Nelson
Timothy J
TJ
Faustino
Randolph S
RS
Behfar
Atta
A
Terzic
Andre
A
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D019070:Cell Lineage; D054377:Chemokine CXCL12 / Q000378:metabolism*; D019295:Computational Biology / Q000379:methods; D004627:Embryonic Induction; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006321:Heart / Q000196:embryology* / Q000254:growth & development; D051379:Mice; D039904:Pluripotent Stem Cells / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D049490:Systems Biology; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism*
D055396:Bone Morphogenetic Protein 2; D054377:Chemokine CXCL12; D012333:RNA, Messenger; D042442:Vascular Endothelial Growth Factors