Fate mapping in mouse demonstrates early secretory differentiation directly from Lgr5+ intestinal stem cells

Area of Science:

• Gastroenterology
• Stem Cell Biology
• Developmental Biology

Background:

• The intestinal epithelium exhibits rapid cell turnover during homeostasis.
• Mechanisms governing stem and progenitor cell behavior for tissue maintenance are not fully understood.

Purpose of the Study:

• To elucidate the cellular orchestration of intestinal crypt maintenance.
• To define the roles of stem and transit-amplifying cells in epithelial renewal.

Main Methods:

• Quantitative fate mapping in three mouse models.
• Mathematical modeling of crypt dynamics.
• Single-cell RNA sequencing.

Main Results:

• A spatially and temporally defined model of crypt maintenance was developed.
• Two cycling populations identified: stem cells and transit-amplifying (TA) cells.
• Fate decisions for secretory and absorptive lineages originate in stem cells.
• TA cell divisions exclusively support the absorptive lineage.

Conclusions:

• Crypt-bottom stem cells are the primary drivers of intestinal epithelium replenishment.
• Stem cells dictate lineage fate, while TA cells amplify absorptive cell production.
• Provides quantitative evidence for stem cell-centric intestinal tissue maintenance.