Mechanisms controlling the acquisition of a cardiac phenotype by liver stem cells

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Abstract
The mechanisms underlying stem cell acquisition of a cardiac phenotype are unresolved. We studied early events during the acquisition of a cardiac phenotype by a cloned adult liver stem cell line (WB F344) in a cardiac microenvironment. WB F344 cells express a priori the transcription factors GATA4 and SRF, connexin 43 in the cell membrane, and myoinositol 1,4,5-triphosphate receptor in the perinuclear region. Functional cell-cell communication developed between WB F344 cells and adjacent cocultured cardiomyocytes in 24 h. De novo cytoplasmic [Ca(2+)](c) and nuclear [Ca(2+)](nu) oscillations appeared in WB F344 cells, synchronous with [Ca(2+)](i) transients in adjacent cardiomyocytes. The [Ca(2+)] oscillations in the WB F344 cells, but not those in the cardiomyocytes, were eliminated by a gap junction uncoupler and reappeared with its removal. By 24 h, WB F344 cells began expressing the cardiac transcription factors Nkx2.5, Tbx5, and cofactor myocardin; cardiac proteins 24 h later; and a sarcomeric pattern 4-6 days later. Myoinositol 1,4,5-triphosphate receptor inhibition suppressed WB F344 cell [Ca(2+)](nu) oscillations but not [Ca(2+)](c) oscillations, and L-type calcium channel inhibition eliminated [Ca(2+)] oscillations in cardiomyocytes and WB F344 cells. The use of these inhibitors was associated with a decrease in Nkx2.5, Tbx5, and myocardin expression in the WB F344 cells. Our findings suggest that signals from cardiomyocytes diffuse through shared channels, inducing [Ca(2+)] oscillations in the WB F344 cells. We hypothesize that the WB F344 cell [Ca(2+)](nu) oscillations activate the expression of a cardiac specifying gene program, ushering in a cardiac phenotype.

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