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Plate IV.313 · Publications

Wnt/PCP-primed intestinal stem cells directly differentiate into enteroendocrine or Paneth cells

Preprint in bioRxiv, 12 August 2020.

PreprintOpen accessStem Cells, Lineage

  1. Anika Böttcher
  2. Maren Büttner
  3. Sophie Tritschler
  4. Michael Sterr
  5. Alexandra Aliluev
  6. Lena Oppenländer
  7. Ingo Burtscher
  8. Steffen Sass
  9. Martin Irmler
  10. Johannes Beckers
  11. Christoph Ziegenhain
  12. Wolfgang Enard
  13. Andrea C. Schamberger
  14. Fien M. Verhamme
  15. Oliver Eickelberg
  16. Fabian J. Theis
  17. Heiko Lickert

Abstract

A detailed understanding of intestinal stem cell (ISC) self-renewal and differentiation is required to better treat chronic intestinal diseases. However, different models of ISC lineage hierarchy 1–6 and segregation 7–12 are debated. Here we report the identification of Lgr5 + ISCs that express Flattop (Fltp), a Wnt/planar cell polarity (PCP) reporter and effector gene. Lineage labelling revealed that Wnt/PCP-activated Fltp + ISCs are primed either towards the enteroendocrine or the Paneth cell lineage in vivo. Integration of time-resolved lineage labelling with genome-wide and targeted single-cell gene expression analysis allowed us to delineate the ISC differentiation path into enteroendocrine and Paneth cells at the molecular level. Strikingly, we found that both lineages are directly recruited from ISCs via unipotent transition states, challenging the existence of formerly predicted bi- or multipotent secretory progenitors 7–12. Transitory cells that mature into Paneth cells are quiescent and express both stem cell and secretory lineage genes, indicating that these cells are the previously described Lgr5 + labelretaining cells 7. Wnt/PCP-activated Lgr5 + ISCs are indistinguishable from Wnt/β-catenin-activated Lgr5 + ISCs based on the expression of stem-cell signature or secretory lineagespecifying genes but possess less self-renewal activity. This suggests that lineage priming and cell-cycle exit is triggered at the post-transcriptional level by polarity cues and a switch from canonical to non-canonical Wnt/PCP signalling. Taken together, we identified the Wnt/PCP pathway as a new niche signal and polarity cue regulating stem cell fate. Active Wnt/PCP signalling represents one of the earliest events in ISC lineage priming towards the Paneth and enteroendocrine cell fate, preceding lateral inhibition and expression of secretory lineagespecifying genes. Thus, our findings provide a better understanding of the niche signals and redefine the mechanisms underlying ISC lineage hierarchy and segregation.

Cite

@misc{bottcher2020wnt,
  title = {{Wnt/PCP-primed intestinal stem cells directly differentiate into enteroendocrine or Paneth cells}},
  author = {Böttcher, Anika and Büttner, Maren and Tritschler, Sophie and Sterr, Michael and Aliluev, Alexandra and Oppenländer, Lena and Burtscher, Ingo and Sass, Steffen and Irmler, Martin and Beckers, Johannes and Ziegenhain, Christoph and Enard, Wolfgang and Schamberger, Andrea C. and Verhamme, Fien M. and Eickelberg, Oliver and Theis, Fabian J. and Lickert, Heiko},
  howpublished = {bioRxiv},
  publisher = {openRxiv},
  year = {2020},
  month = aug,
  doi = {10.1101/2020.08.12.247585},
  url = {https://doi.org/10.1101/2020.08.12.247585},
  note = {Preprint}
}
.bib file