1. Centre Development in Stem Cell Biology, Institute for Stem Cell Research, University of Edinburgh, Edinburgh, EH9 3JQ, UK
2. Institute for Stem Cell Biology University of Cambridge, Cambridge, CB2 1QT, UK

Correspondence to: Austin Smith^1,2 Correspondence and requests for materials should be addressed to A.S. (Email: austin.smith@ed.ac.uk).

Through cell fusion, embryonic stem (ES) cells can erase the developmental programming of differentiated cell nuclei and impose pluripotency^{1, 2}. Molecules that mediate this conversion should be identifiable in ES cells. One candidate is the variant homeodomain protein Nanog, which has the capacity to entrain undifferentiated ES cell propagation^{3, 4}. Here we report that in fusions between ES cells and neural stem (NS) cells, increased levels of Nanog stimulate pluripotent gene activation from the somatic cell genome and enable an up to 200-fold increase in the recovery of hybrid colonies, all of which show ES cell characteristics. Nanog also improves hybrid yield when thymocytes or fibroblasts are fused to ES cells; however, fewer colonies are obtained than from ES NS cell fusions, consistent with a hierarchical susceptibility to reprogramming among somatic cell types. Notably, for NS ES cell fusions elevated Nanog enables primary hybrids to develop into ES cell colonies with identical frequency to homotypic ES ES fusion products. This means that in hybrids, increased Nanog is sufficient for the NS cell epigenome to be reset completely to a state of pluripotency. We conclude that Nanog can orchestrate ES cell machinery to instate pluripotency with an efficiency of up to 100% depending on the differentiation status of the somatic cell.

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