Intestinal label-retaining cells are secretory precursors expressing Lgr5

Abstract

The rapid cell turnover of the intestinal epithelium is achieved from small numbers of stem cells located in the base of glandular crypts. These stem cells have been variously described as rapidly cycling or quiescent. A functional arrangement of stem cells that reconciles both of these behaviours has so far been difficult to obtain. Alternative explanations for quiescent cells have been that they act as a parallel or reserve population that replace rapidly cycling stem cells periodically or after injury; their exact nature remains unknown. Here we show mouse intestinal quiescent cells to be precursors that are committed to mature into differentiated secretory cells of the Paneth and enteroendocrine lineage. However, crucially we find that after intestinal injury they are capable of extensive proliferation and can give rise to clones comprising the main epithelial cell types. Thus, quiescent cells can be recalled to the stem-cell state. These findings establish quiescent cells as an effective clonogenic reserve and provide a motivation for investigating their role in pathologies such as colorectal cancers and intestinal inflammation.

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

“…This Lgr5 + stem cell population also gives continuous rise to a quiescent label-retaining population, located at the +4 position and expressing Lgr5, that is committed to mature into Paneth and enteroendocrine cells, but which can alternatively be recalled to the stem cell state within the crypt in instances of injury to the crypt (Sangiorgi and Capecchi, 2008;Montgomery et al, 2011;Takeda et al, 2011;Tian et al, 2011;Buczacki et al, 2013;Clevers, 2013). ISCs feed into transit-amplifying cells, which serve as the forerunners of the differentiated intestinal epithelial cell (IEC) types (Barker et al, 2007).…”

Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity

“…The result implies that phenotypic changes (or demise) of ISCs impacts on transcriptional profiles of other crypts cells. The fact that (partial) loss of ISCs did not affect the tissue architecture is in accord with previous studies describing the effects of diphtheria toxin‐mediated elimination of ISCs (Buczacki et al ., 2013; Tian et al ., 2011). These studies showed that epithelial cells retain remarkable plasticity and upon ISC loss, crypt cells positioned above the stem and Paneth cell compartment can revert their phenotype and functionally substitute for the lost ISCs.…”

“…These studies showed that epithelial cells retain remarkable plasticity and upon ISC loss, crypt cells positioned above the stem and Paneth cell compartment can revert their phenotype and functionally substitute for the lost ISCs. These ISC‐substituting cells might be precursors of Paneth cells or other secretory lineages (Buczacki et al ., 2013; Roth et al ., 2012; van Es et al ., 2012b) or TA cells (Asfaha et al ., 2015). …”

Microenvironmental control of stem cell fate in intestinal homeostasis and disease

“…Further work showed that Bmi1 is in fact expressed broadly throughout the crypt, diminishing this as a specific stem cell marker 15, 16, 17. Rather than relying on putative marker expression, Buczacki et al focused on cells with functional label retention properties and in a series of elegant experiments, demonstrated that these cells are committed secretory cell precursors that retain the capability of returning to stem cell function in the event of intestinal damage and regeneration 18. Numerous other markers have been used to identify populations that are enriched for cells capable of lineage tracing in the intestine including Tert , Hopx , Lrig1 , Sox9 , Ascl2 , Olfm4 , Prom1 , and Rnf43 15, 19, 20, 21, 22.…”