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Disruption of apical-basal polarity of human embryonic stem cells enhances hematoendothelial differentiation.

Krtolica A, Genbacev O, Escobedo C, Zdravkovic T, Nordstrom A, Vabuena D, Nath A, Simon C, Mostov K, Fisher SJ

Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94143, USA.

During murine development, the formation of tight junctions and acquisition of polarity are associated with allocation of the blastomeres on the outer surface of the embryo to the trophoblast lineage, whereas the absence of polarization directs cells to the inner cell mass. Here, we report the results of ultrastructural analyses that suggest a similar link between polarization and cell fate in human embryos. In contrast, the five human embryonic stem cell (hESC) lines displayed apical-basal, epithelial-type polarity with electron-dense tight junctions, apical microvilli, and asymmetric distribution of organelles. Consistent with these findings, molecules that are components of tight junctions or play regulatory roles in polarization localized to the apical regions of the hESCs at sites of cell-cell contact. The tight junctions were functional, as shown by the ability of hESC colonies to exclude the pericellular passage of a biotin compound. Depolarization of hESCs produced multilayered aggregates of rapidly proliferating cells that continued to express transcription factors that are required for pluripotency at the same level as control cells. However, during embryoid body formation, depolarized cells differentiated predominantly along mesenchymal lineage and spontaneously produced hematoendothelial precursors more efficiently than control ESC. Our findings have numerous implications with regard to strategies for deriving, propagating, and differentiating hESC.

Published 7 September 2007 in Stem Cells, 25(9): 2215-23.
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