Abstract
Polarity cues regulate intestinal stem cell fate. Bottcher et al. demonstrate that mouse intestinal stem cells, which express the Wnt/planar cell polarity reporter Flattop, are primed either towards the enteroendocrine or Paneth cell lineage. A detailed understanding of intestinal stem cell (ISC) self-renewal and differentiation is required to treat chronic intestinal diseases. However, the different models of ISC lineage hierarchy(1-6) and segregation(7-12) are subject to debate. Here, we have discovered non-canonical Wnt/planar cell polarity (PCP)-activated ISCs that are primed towards the enteroendocrine or Paneth cell lineage. Strikingly, integration of time-resolved lineage labelling with single-cell gene expression analysis revealed 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(+) label-retaining cells(7). Finally, Wnt/PCP-activated Lgr5(+) ISCs are molecularly indistinguishable from Wnt/beta-catenin-activated Lgr5(+) ISCs, suggesting 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 redefine the mechanisms underlying ISC lineage hierarchy and identify the Wnt/PCP pathway as a new niche signal preceding lateral inhibition in ISC lineage priming and segregation.
| Item Type: | Journal article |
|---|---|
| Faculties: | Biology |
| Subjects: | 500 Science > 570 Life sciences; biology |
| ISSN: | 1465-7392 |
| Language: | English |
| Item ID: | 97098 |
| Date Deposited: | 05. Jun 2023, 15:25 |
| Last Modified: | 17. Oct 2023, 14:54 |
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