Studies on lipid signals associated with differentiation propensity in mouse ES cells

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An understanding of the mechanism that regulates the cardiac differentiation of pluripotent stem cells is necessary for the effective generation and expansion of cardiomyocytes as cell therapy products. We isolated P19CL6 cell sublines that possess distinct properties in cardiomyogenesis and extracted 24 cardiomyogenesis-related candidate (CMR) genes correlated with cardiomyogenesis using a transcriptome analysis. Knockdown of the CMR genes by RNAi revealed that 18 CMR genes influence spontaneous contraction or transcript levels of cardiac marker genes in embryonal carcinoma (EC) cells. We also performed knockdown of the CMR genes in mouse embryonic stem (ES) cells and induced in vitro cardiac differentiation. Three CMR genes, AW551984, Prostamide/prostaglandin F synthase and Cd302, modulated the cardiac differentiation of both EC cells and ES cells. Depletion of AW551984 attenuated the expression of early cardiac transcription factor Nkx2.5 without affecting transcript levels of pluripotency and early mesoderm marker genes during ES cell differentiation. Activation of Wnt/β-catenin signaling enhanced the expression of both AW551984 and Nkx2.5 in ES cells during embryoid body formation. Our findings indicate that AW551984 is a novel regulator of cardiomyogenesis from pluripotent embryonic cells, which links Wnt/β-catenin signaling to Nkx2.5 expression.