Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia

The transition zones of the squamous and columnar epithelia constitute hotspots for the emergence of cancer, often preceded by metaplasia, in which one epithelial type is replaced by another. It remains unclear how the epithelial spatial organization is maintained and how the transition zone niche is remodelled during metaplasia. Here we used single-cell RNA sequencing to characterize epithelial subpopulations and the underlying stromal compartment of endo- and ectocervix, encompassing the transition zone. Mouse lineage tracing, organoid culture and single-molecule RNA in situ hybridizations revealed that the two epithelia derive from separate cervix-resident lineage-specific stem cell populations regulated by opposing Wnt signals from the stroma. Using a mouse model of cervical metaplasia, we further show that the endocervical stroma undergoes remodelling and increases expression of the Wnt inhibitor Dickkopf-2 (DKK2), promoting the outgrowth of ectocervical stem cells. Our data indicate that homeostasis at the transition zone results from divergent stromal signals, driving the differential proliferation of resident epithelial lineages.

Automated summary

The transition zones of squamous and columnar epithelia are prone to cancer, often associated with metaplasia. Through mouse models and single-cell RNA sequencing, it was discovered that the cervical epithelial cells in the endo- and ectocervix have distinct origins from stem cells regulated by opposing Wnt signals from the stroma. Additionally, a mouse model of cervical metaplasia showed that the stroma in the endocervix undergoes remodeling and increases expression of the Wnt inhibitor DKK2, promoting the outgrowth of ectocervical stem cells.