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Stem cells

Equilibrium established

Nature volume 521, pages 299300 (21 May 2015) | Download Citation

Pluripotent cells can produce all cell types in the body. It emerges that this state of potential is endowed by cues, including inhibition of Wnt signalling, that maintain a balance between diverse cellular outcomes. See Article p.316

Achieving dualism — a state in which two opposing forces coexist in balance — is central to Taoist philosophy, and, it has now emerged, to stem cells too. Stem cells reside at a nexus of opportunity, harbouring the potential to form myriad tissues, from blood to bone to brain. Balancing these diverse potentials is key to endowing and maintaining stem-cell identity1. On page 316 of this issue, Wu et al.2 show that neutralizing one cellular signalling pathway, Wnt, helps stem cells to achieve such balance.

Stem cells that can form all bodily tissue types are said to be pluripotent3. Pluripotency is not a singular state, but is a property of at least two related developmental cell types. The first pluripotent cells to arise in mouse embryos have broad cellular potential and are dubbed naive4. Soon after naive cells form, they become primed for differentiation4, as many extracellular signals, including Fgf and Wnt proteins, direct them to become one of various specialized cell types. Specifically, primed pluripotent cells can become either ectoderm (the progenitor to skin and brain tissue) or mesendoderm (the progenitor to blood, bone, intestines and other organs)3 (Fig. 1a).

Figure 1: Stabilizing the stem-cell seesaw.
Figure 1

a, During normal development, naive pluripotent cells, which have the potential to give rise to all bodily cell types, mature into unstable primed pluripotent cells. These primed cells differentiate into more-specialized cell types (mesendoderm or ectoderm) in response to various signalling pathways. Fgf signalling and Wnt signalling both block ectoderm formation while promoting mesendoderm formation. b, Wu et al.2 demonstrate that primed pluripotent cells are perched on a precarious seesaw between mesendoderm and ectoderm fates. By providing Fgf signals and simultaneously inhibiting Wnt signals, primed pluripotent cells can be stabilized.

Because primed pluripotent cells are poised to undergo imminent differentiation, they exist in a precarious position1. If taken from an embryo and cultivated in a Petri dish, primed cells often spontaneously lose pluripotency, and develop into differentiated cell types5. This is partly attributable to the action of Wnt and Fgf proteins, which both induce mesendoderm differentiation and block ectoderm formation (Fig. 1a)6,7.

Primed pluripotent cells produce Wnt, and might thereby intrinsically prompt their own differentiation5,8,9. Wu et al. thus reasoned that they could block mesendoderm differentiation in this cell type by blocking Wnt5,10,11and simultaneously restrict ectoderm formation by supplying Fgf (Fig. 1b). By stabilizing a seesaw of opposing lineage forces, an uncommitted pluripotent state might be realized at the fulcrum. The authors found that such treatment broadly 'stabilized' primed pluripotent cells, whether of human, macaque, chimpanzee or mouse provenance.

To investigate whether primed pluripotent cells stabilized in this manner retain the potential to develop into ectodermal and mesendodermal cells, Wu et al. grafted stabilized human pluripotent stem cells onto 7.5-day-old post-implantation mouse epiblasts placed in a Petri dish (epiblasts are isolated, non-intact embryonic tissue fragments that lack supporting tissues and are therefore not viable). Strikingly, the stabilized human pluripotent cells successfully integrated into these mouse epiblasts, and the engrafted cells seemed to resume their natural developmental programme, differentiating into cells that expressed human ectoderm- and mesendoderm-specific genes in the confines of the epiblast. Although the full repertoire of the developmental genes expressed awaits a more extensive analysis, these findings imply that stabilized pluripotent cells are still capable of differentiation once released from stabilizing conditions.

Do the stabilized pluripotent cells correspond to any natural cellular state on the timeline of in vivo development? The classification of pluripotent cells as either naive or primed is probably an artificial dichotomy, and, indeed, gene expression in the Wnt-inhibitor-grown cells differs from that of either naive or primed pluripotent cells. Does this mean that such stabilized cells are genuinely a different class of pluripotent cell, or do they simply represent a more stabilized type of primed pluripotency, owing to a rebalancing of competing lineage forces? Perhaps 'stabilized' primed pluripotency is short-lived in vivo because of the speed of embryonic development, complicating efforts to assign in vivo counterparts to these cells. Some evidence10 argues that the stabilized cells correspond to an intermediate between naive and primed pluripotency.

A final possibility is that Wu and colleagues' cells exist orthogonally to the natural developmental timeline — that is, they are an artificial, non-developmental cell type. Maybe the priming of these cells has not been rewritten by Wnt inhibition at all. Instead, a change in adhesion properties could enable the stabilized human cells to engraft into the isolated mouse epiblast in vitro. Perhaps reflecting some degree of artificiality, the stabilized cells engraft only into the posterior of such epiblasts, whereas conventional primed cells from mice can engraft into all regions. This bias remains unexplained.

Finally, we propose that the idea of lineage balance1 might not be specific to pluripotent stem cells, but might also extend to more-specialized ones, such as gut12 or blood13 stem cells. If stem cells represent a state in which opposing lineage potentials coexist, then negotiating a balance in competing lineage forces might prove decisive in stabilizing and thus capturing diverse types of stem cell.



  1. 1.

    & Cell Stem Cell 8, 363–369 (2011).

  2. 2.

    et al. Nature 521, 316–321 (2015).

  3. 3.

    , & Physiol. Rev. 95, 245–295 (2015).

  4. 4.

    & Cell Stem Cell 4, 487–492 (2009).

  5. 5.

    et al. Development 141, 1209–1221 (2014).

  6. 6.

    et al. EMBO J. 30, 4874–4884 (2011).

  7. 7.

    et al. Cell Stem Cell 14, 237–252 (2014).

  8. 8.

    , , , & Nature Commun. 3, 1070 (2012).

  9. 9.

    et al. Stem Cell Rep. 4, 744–757 (2015).

  10. 10.

    et al. Stem Cell Rep. 4, 114–128 (2015).

  11. 11.

    , , & PLoS ONE 8, e63378 (2013).

  12. 12.

    et al. Nature Meth. 11, 106–112 (2014).

  13. 13.

    et al. Science 345, 1509–1512 (2014).

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  1. Kyle M. Loh is in the Department of Developmental Biology and at the Stanford Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.

    • Kyle M. Loh
  2. Bing Lim is at Merck Research Laboratories, Translational Medicine Research Centre, Singapore 138665.

    • Bing Lim


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Correspondence to Kyle M. Loh or Bing Lim.

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