Human embryonic stem cells (hESCs) expressing pluripotency markers are assumed to possess equipotent developmental potential. However, disparate responses to differentiation stimuli functionally illustrate that hESCs generate a spectrum of differentiated cell types, suggestive of lineage bias. Here, we reveal specific cell surface markers that allow subfractionation of hESCs expressing hallmark markers of pluripotency. By direct de novo isolation of these subsets, we demonstrate that propensities for lineage differentiation are balanced with reduced clonogenic self-renewal. Histone modification marks of gene loci associated with pluripotency versus lineage specificity predicted cell fate potential of these subfractions, thereby supporting the absence of uniform bivalency as a molecular paradigm to describe cell fate determination of pluripotent cells. Our study reveals that cell fate potential is encoded within cells comprising hESC cultures, highlighting them as a means to understand the mechanisms of lineage specification of pluripotent cells.
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