Design principles of small intestinal crypt maintenance

Abstract

The intestinal epithelium has a remarkably high turnover in homeostasis. It remains unresolved how turnover is orchestrated at the cellular level and how the behaviour of stem and progenitor cells ensures tissue maintenance. To address this, we combined quantitative fate mapping in three complementary mouse models with mathematical modelling and single-cell RNA sequencing. Our integrated approach generated a spatially and temporally defined model of crypt maintenance that is based on two cycling populations: crypt-based columnar (CBC) and transit amplifying (TA) cells. Validation experiments substantiated the predictions from the model revealing TA cells as the major contributor to the absorptive lineage, while balanced CBC cell fate choices controlled the numbers of cells in the secretory lineage. By unravelling these mechanisms, we gain insights into the process of tissue turnover and provide direct evidence to support the notion of CBC cells as the major driver of the intestinal epithelium replenishment. HighlightsO_LISpatially and temporally resolved cellular model of small intestinal crypt maintenance. C_LIO_LIStem cells exhibit predisposition towards secretory fate. C_LIO_LISecretory lineage has a limited contribution to the high turnover of intestinal epithelium. C_LIO_LICellular differentiation within the crypt occurs rapidly within 72 hours. C_LI