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Non-canonical Wnt/PCP signalling regulates intestinal stem cell lineage priming towards enteroendocrine and Paneth cell fates.

Nat. Cell Biol. 23, 23-31 (2021)
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Open Access Green
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 hierarchy1–6 and segregation7–12 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 progenitors7–12. 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 cells7. Finally, Wnt/PCP-activated Lgr5+ ISCs are molecularly indistinguishable from Wnt/β-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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Label-retaining Cells; Progenitor Cells; Gene Ontology; Mouse Line; In-vivo; Expression; Distinct; Identification; Polarity; Numbers
ISSN (print) / ISBN 1465-7392
e-ISSN 1476-4679
Quellenangaben Volume: 23, Issue: 1, Pages: 23-31 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Heidelberger Platz 3, Berlin, 14197, Germany
Reviewing status Peer reviewed
Grants Initiative and Network Fund of the Helmholtz Association
European Union
Helmholtz Society
Helmholtz Portfolio Theme 'Metabolic Dysfunction and Common Disease'
Helmholtz Alliance 'Aging and Metabolic Programming, AMPro'
Helmholtz Alliance ICEMED-Imaging and Curing Environmental Metabolic Diseases
Helmholtz Association's Initiative and Networking Fund through Helmholtz AI
German Research Foundation
German Center for Diabetes Research (DZD e.V.)
Emmy-Noether Fellowship