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)

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

TissueStem CellMarked byReferences
 Intestine Crypt base columnar cell Lgr5 Barker 2007
 Mammary gland Basal cell Axin2, Lgr5, Procr Van Amerongen 2012, De Visser 2012, Wang 2015, Plaks 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 2008, Lim et al 2016
 Kidney Nephron segment-specific stem cell Lgr5, Axin2 Barker 2012, Rinkevich 2014
 Cochlea Tympanic border cell Axin2, Lgr5 Jan 2013, Shi 2013
 OvaryHilum 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
TestisSpermatogonial stem cellAxin2Takase et al, 2016