Endogenous Wnt signalling in human embryonic stem cells generates an equilibrium of distinct lineage-specified progenitors

Timothy A. Blauwkamp, Shelly Nigam, Reza Ardehali, Irving L. Weissman and Roel Nusse ()
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Timothy A. Blauwkamp: Howard Hughes Medical Institute, Lorry Lokey Stem Cell Research Building, Stanford University
Shelly Nigam: Howard Hughes Medical Institute, Lorry Lokey Stem Cell Research Building, Stanford University
Reza Ardehali: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University
Irving L. Weissman: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University
Roel Nusse: Howard Hughes Medical Institute, Lorry Lokey Stem Cell Research Building, Stanford University

Nature Communications, 2012, vol. 3, issue 1, 1-10

Abstract: Abstract The pluripotent nature of human embryonic stem cells (hESCs) makes them convenient for deriving therapeutically relevant cells. Here we show using Wnt reporter hESC lines that the cells are heterogeneous with respect to endogenous Wnt signalling activity. Moreover, the level of Wnt signalling activity in individual cells correlates with differences in clonogenic potential and lineage-specific differentiation propensity. The addition of Wnt protein or, conversely, a small-molecule Wnt inhibitor (IWP2) reduces heterogeneity, allowing stable expansion of Wnthigh or Wntlow hESC populations, respectively. On differentiation, the Wnthigh hESCs predominantly form endodermal and cardiac cells, whereas the Wntlow hESCs generate primarily neuroectodermal cells. Thus, heterogeneity with respect to endogenous Wnt signalling underlies much of the inefficiency in directing hESCs towards specific cell types. The relatively uniform differentiation potential of the Wnthigh and Wntlow hESCs leads to faster and more efficient derivation of targeted cell types from these populations.

Date: 2012
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DOI: 10.1038/ncomms2064

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