It's not every day that a respected laboratory simultaneously characterizes a novel adult stem cell, overturns an earlier identification of a different stem-cell candidate, pounds a nail into the coffin of an existing hypothesis about how adult stem cells can be identified, and finds a surface marker that — all by itself — may prove useful in identifying numerous other adult stem-cell types.

Intestinal epithelium, the most rapidly renewing tissue in adult mammals, consists of four main differentiated cell types — the majority enterocytes along with secretory goblet cells, Paneth cells and enteroendocrine cells. Hans Clevers at the Hubrecht Institute, Utrecht, The Netherlands, and his colleagues now think that they have identified the intestinal stem cell, which — in contrast to what had been thought for several years — sits at the base of the crypts in the intestinal wall and has quite different identifying markers from the cell type previously believed to be playing that very role. These are the rare cells called crypt base columnar (CBC) cells: sparse, slender, dividing cells that are sandwiched between the bulkier Paneth cells at the bottom of intestinal crypts. A feature unique to CBCs is their display of the cell-surface marker Lgr5, a transmembrane protein whose expression is under the control of the Wnt pathway1.

Easily differentiated from the neighboring Paneth cells both morphologically and through their staining properties, CBC cells were observed by the Utrecht group to divide about once a day. Using heterozygous mice with knock-in Lgr5 alleles coupled to a reporter genes, the team carried out lineage-tracing experiments in mouse small intestine for up to 60 days and found that CBC cells — defined by their expression of the Lgr5-linked reporter gene— differentiated into all four intestinal cell types. Similar experiments showed that CBC cells serve the same stem-cell function in the colon, for which no stem cell candidate has previously been put forth.

Identifying CBC cells as stem cells puts a big question mark over another candidate for the intestinal stem cell. This cell type is morphologically quite distinct from CBCs and is located a little higher up in the crypt wall. Its putative identification as a stem cell was based on its apparent propensity to retain labelled DNA, instead of the labelled strands getting distributed at random among the progeny cells. This feature played to the 'immortal-strand' hypothesis: an idea, never proved, that through successive rounds of DNA replication and cell division, the stem-cell daughter always retains an original DNA strand, thereby ensuring an organism's genetic integrity.

The functional identification of CBC cells as stem cells by Clevers and his team is another blow for the immortal-strand hypothesis, which is looking increasingly shaky after a recent demonstration by a group led by Sean Morrison at the University of Michigan in Ann Arbor that hematopoietic stem cells, the best understood of adult stem cells, do not retain labeled DNA upon asymmetric division.2

Tantalizingly, the stem-cell marker that Clevers's team has identified, Lgr5, is also observed in rare scattered cells in the eye, brain, hair follicle, mammary gland, reproductive organs, and stomach of the adult mouse. Lgr5-positive cells have also been found in colorectal, ovarian and hepatocellular carcinomas, leading the authors to suspect that Lgr5 may prove useful in identifying stem cells in both healthy tissue and tumours.