Progenitor cell location as determinant of fate, regeneration and transformation

In many stem cell niches, stem cells are tucked away in anatomically distinct locations, enabling exclusive interactions with niche signals that maintain stemness and prevent differentiation. In structurally simple epithelia such as the esophagus, no local stem cell niches have yet been identified.

In line with the apparent lack of local esophageal microenvironments, a single progenitor cell population is suggested to maintain the epithelia during homeostasis and to be the cell-of-origin in squamous cell carcinomas.

We have, for the first time, identified functional heterogeneity within the esophageal progenitor population linked to a proximal-distal signaling gradient.

Furthermore, we have identified enrichment of renewing progenitor cells in specialized distal micro-niches associated with folding of the epithelial sheet.

Here we exploit quantitative in vivo lineage tracing followed by mathematical modelling, single cell/nuclei sequencing, spatial transcriptomics and organoid co-cultures in mouse and human esophagi to identify and functionally characterize how local signaling environments (stem cell niches) influence progenitor fate normally and upon regenerative or transformative challenges.