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Dll1+ secretory progenitor cells revert to stem cells upon crypt damage

Abstract

Lgr5+ intestinal stem cells generate enterocytes and secretory cells. Secretory lineage commitment requires Notch silencing. The Notch ligand Dll1 is expressed by a subset of immediate stem cell daughters. Lineage tracing in Dll1GFPiresCreERT2 knock-in mice reveals that single Dll1high cells generate small, short-lived clones containing all four secretory cell types. Lineage specification thus occurs in immediate stem cell daughters through Notch lateral inhibition. Cultured Dll1high cells form long-lived organoids (mini-guts) on brief Wnt3A exposure. When Dll1high cells are genetically marked before tissue damage, stem cell tracing events occur. Thus, secretory progenitors exhibit plasticity by regaining stemness on damage.

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Figure 1: Dll1 expression by rare undifferentiated transit-amplifying cells above the Paneth/stem cell zone.
Figure 2: Lineage tracing in the intestine of the Dll1GFPiresCreERT2R26RLacZ mice.
Figure 3: Intestinal Dll1+ cells are secretory lineage precursors.
Figure 4: Dll1 precursors can convert to intestinal stem cells in vitro.
Figure 5: Dll1 precursors can convert into intestinal stem cells in vivo.

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Acknowledgements

This research was supported by KWF/HUBR2005-3237 (T.S.), KWF/HUBR2005-3956 (L.Z.), EU/Health-F4-2007-200720 (M.v.d.W.), NIH/NCI Physical Sciences Oncology Center at MIT: U54CA143874 (A.L. and A.v.O.), TI Pharma T3-106 (J.H.v.E. and M.v.d.B.) and NIRM (N.S.).

We thank D. Stange for critically reading the manuscript.

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Contributions

J.H.v.E., T.S. and H.C. conceived and designed the experiments, J.H.v.E., T.S., M.v.d.W., A.L., A.G. L.Z., M.v.d.B., J.K., A.C.M.M., A.v.O., N.B. and A.N.Y.N. performed the experiments, J.H.v.E., T.S. M.v.d.W., A.L., A.v.O. and H.C. analysed the data, J.H.E. and H.C. wrote the paper.

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Correspondence to Hans Clevers.

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van Es, J., Sato, T., van de Wetering, M. et al. Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol 14, 1099–1104 (2012). https://doi.org/10.1038/ncb2581

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