PT  - JOURNAL ARTICLE
AU  - Laura E. Sanman
AU  - Ina W. Chen
AU  - Jake M. Bieber
AU  - Veronica Steri
AU  - Byron Hann
AU  - Lani F. Wu
AU  - Steven J. Altschuler
TI  - Non-stem progenitors enable coordinated changes in gut epithelial cell-type composition
AID  - 10.1101/840371
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 840371
4099  - http://biorxiv.org/content/early/2019/11/13/840371.short
4100  - http://biorxiv.org/content/early/2019/11/13/840371.full
AB  - Renewing tissues have the remarkable ability to maintain both proliferative progenitor and specialized mature cell types at consistent ratios. How are complex milieus of microenvironmental signals interpreted to coordinate tissue cell-type composition? Here, we develop a high-throughput approach, combining organoid technology, combinatorial perturbations, and quantitative imaging to address these questions in the context of the intestinal epithelium. We find that changes in proliferation of transit-amplifying (TA) cells, but not Lgr5+ stem cells, alters the composition of mature secretory and absorptive cell-types in organoids and in vivo. The link between TA proliferation and mature fate bias arises from differential amplification of secretory and absorptive progenitor cells. Further, TA cells have a distinct pattern of regulation from other epithelial cell-types that stems, in part, from signal integration via the MEK-Erk pathway and paracrine BMP production. These results demonstrate that TA cells, a feature of many renewing tissues, play a critical role in converting complex microenvironmental signals into changes in cell-type composition.