Intestinal Crypt Homeostasis Results from Neutral Competition between Symmetrically Dividing Lgr5 Stem Cells

Abstract

Intestinal stem cells, characterized by high Lgr5 expression, reside between Paneth cells at the small intestinal crypt base and divide every day. We have carried out fate mapping of individual stem cells by generating a multicolor Cre-reporter. As a population, Lgr5(hi) stem cells persist life-long, yet crypts drift toward clonality within a period of 1-6 months. We have collected short- and long-term clonal tracing data of individual Lgr5(hi) cells. These reveal that most Lgr5(hi) cell divisions occur symmetrically and do not support a model in which two daughter cells resulting from an Lgr5(hi) cell division adopt divergent fates (i.e., one Lgr5(hi) cell and one transit-amplifying [TA] cell per division). The cellular dynamics are consistent with a model in which the resident stem cells double their numbers each day and stochastically adopt stem or TA fates. Quantitative analysis shows that stem cell turnover follows a pattern of neutral drift dynamics.

Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating–cancer stem cells: distinct, overlapping or same populations

“…Both would be long lived, give rise to each other, insuring the constancy of the population by a sophisticated retrocontrol (that is, reversible phenotypes; Li and Clevers, 2010). Such a dynamic equilibrium between stem cells has also been demonstrated in intestinal crypts (Lopez-Garcia et al, 2010;Snippert et al, 2010).…”

Microenvironmental control of stem cell fate in intestinal homeostasis and disease

“…Elegant work by the Winton and Clevers groups has shown that murine intestinal stem cells form an equipotent population that undergoes stochastic clone extinction, compensated by expansion and replacement by a neighbouring cell. This random enlargement and contraction of clones, known as neutral drift dynamics, can lead to stochastic clonal extinction or niche succession, where one clone expands to fill the entire niche 31, 32. Similar neutral drift dynamics are seen in human colon using mtDNA mutations as clonal markers 33.…”

Intestinal stem cell proliferation and epithelial homeostasis in the adult Drosophila midgut

“…ISCs can divide both symmetrically and asymmetrically. A combined approach of mathematical modeing and genetic experiments suggest that, as in the mouse intestinal epithelium (Snippert et al, 2010), ISCs in the adult Drosophila midgut can devide symetrically and stochastically give rise to either two stem cells or two differentiated daughter cells (de Navascues et al, 2012). On the other hand, integrin-dependent adhesion to the basal membrane-leading to apical localization of the Par complex-and assymetric localisation of Sara endosomes contribute to Notch signalling bias and assymetric division of ICSs to produce EBs (Goulas et al, 2012) (Montagne and Gonzalez-Gaitan, 2014).…”