Abstract
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.
Highlights
Despite extensive self-organization abilities, the mucosal epithelial homeostasis is maintained by the local microenvironment, defined by complex interactions between epithelium and stroma
Having illuminated the signalling pathways and cellular components involved in stemness and differentiation of the ectocervical squamous epithelium, we examined their role in the emergence of squamous metaplasia
When tissue integrity is disturbed due to infections or other assaults, the disturbance is usually followed by substantial reorganizations of the niche, facilitating the restoration of tissue homeostasis[50]
Summary
Despite extensive self-organization abilities, the mucosal epithelial homeostasis is maintained by the local microenvironment, defined by complex interactions between epithelium and stroma. The earliest recognized sign of squamous metaplasia is the appearance of cuboidal cells beneath the columnar endocervical epithelium next to the transition zone. Our study unravels the cervical cell subsets and reveals two committed adult epithelial stem cell types, which give rise to either squamous or columnar epithelial lineages. Homeostasis of these different epithelia at the SCJ is regulated by opposing Wnt gradients, and a shift towards a Wnt-repressive microenvironment drives squamous metaplasia
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