Stem Cells and Wnt Signaling

Stem cells are defined as having the capacity to self-renew while also producing specialized cells. Thereby, stem cells retain their developmental potential over the long term. Lineage tracing based on Wnt target genes such as Lgr5 and Axin2 have provided evidence for Wnts as critical stem cell signals. Wnt-target gene labeled stem cells have been detected in organs ranging from the intestine to the stomach, the skin, the hair follicle, and the mammary gland (see table below and figure, right). These choices of stem cells to self-renew or to differentiate are dictated by extrinsic signals with a short range of action, thereby limiting the number of stem cells in tissues. The signals and the cells that produce them are known as the niche. Wnt signals, lipid modified and therefore restricted in their range of action, are widely implicated as niche factors (reviewed by Clevers, Loh, Nusse 2014, PDF).

The mechanism by which Wnt signals maintain stem cells may include a block in differentiation, possibly by suppressing differentiation-specific genes. Differentiation is thought to be the default step of a dividing stem cell.

The implications of the connection between Wnt and stem cells include the use of Wnt proteins or Wnt agonists to maintain stem cells in culture. While stem cells are difficult to expand in a self-renewing state, adding Wnts or R-Spondins has overcome some of these problems (Zeng 2010, Sato 2009).


A clone of Axin2-labeled cells in mouse skin tissue (from Lim 2013)

Wnt-responsive tissue stem cells identified by means of lineage tracing (based on Clevers, Loh, Nusse 2014, PDF)

Stem Cell
Marked by
 Intestine  Crypt base columnar cell  Lgr5  Barker 2007
 Mammary gland  Basal cell  Axin2, Lgr5, Procr  Van Amerongen 2012De Visser 2012Wang 2015Plaks 2013
 Stomach  Basal pyloric cell  Lgr5  Barker 2010
 Interfollicular epidermis  Basal cell  Axin2  Lim 2013
 Central nervous system  Radial glial cell  Axin2  Bowman 2013
 Hair follicle  Outer bulge cell  Lgr5, Axin2  Jaks 2008Lim et al 2016
 Kidney  Nephron segment-specific stem cell  Lgr5, Axin2  Barker 2012Rinkevich 2014
 Cochlea  Tympanic border cell  Axin2, Lgr5  Jan 2013Shi 2013
 Ovary Hilum ovarian surface epithelial cell  Lgr5  Flesken-Nikitin 2013, Ng 2014
 Taste bud  Circumvallate papilla stem cell  Lgr5  Yee 2013
 Liver  Pericentral hepatocyte  Axin2  Wang 2015
 Bone  Osteoblast  Axin2  Tan 2014
 Embryonic stem  Embryonic stem  Axin2  Ten Berge 2011
Testis Spermatogonial stem cell Axin2 Takase et al, 2016