Fate mapping in mouse demonstrates early secretory differentiation directly from Lgr5+ intestinal stem cells
Isidora Banjac, Martti Maimets, Ingrid H C Tsang, Marius Dioli, Stine L. Hansen, Kata Krizic, Raul Bardini Bressan, Cecilia Lövkvist, Kim B. Jensen
Abstract
The intestinal epithelium has a remarkably high turnover in homeostasis. It remains unresolved how this is orchestrated at the cellular level and how the behavior of stem and progenitor cells ensures tissue maintenance. To address this, we combined quantitative fate mapping in three complementary mouse models with mathematical modeling and single-cell RNA sequencing. Our integrated approach generated a spatially and temporally defined model of crypt maintenance based on two cycling populations: stem cells at the crypt-bottom and transit-amplifying (TA) cells above them. Subsequently, we validated the predictions from the mathematical model, demonstrating that fate decisions between the secretory and absorptive lineages are made within the stem cell compartment, whereas TA cell divisions contribute specifically to the absorptive lineage. These quantitative insights provide further direct evidence for crypt-bottom stem cells as the dominant driver of the intestinal epithelium replenishment. • Quantitative insights in cell behavior and fate segregation in the intestine • Stem cell fate choices control proportions between absorptive and secretory cells • Stem cells are predisposed toward secretory fate • Cell lineages within the crypt are segregated within 72 h Banjac et al. show that Lgr5-expressing intestinal stem cells are the primary source of homeostatic tissue replenishment. The study demonstrates that stem cells located at the bottom of crypts will either differentiate directly into one of four secretory cell types or generate a highly proliferative absorptive progenitor.