Wnt/beta catenin in regenerating liver ! stem cells everywhere !

Pittsburgh, PA -

The Wnt pathway is involved in tissue morphogenesis and has been found activated in various stem cell types and cancers. In a recent paper (Apte et al. Wnt/beta-catenin signaling mediates oval cell response in rodents. Hepatology. 2007 Oct 10) it was demonstrated that this pathway is activated in adult liver stem cells (oval cells) after liver damage.

To induce liver damage, rats were treated with a hepatotoxin and underwent partial resection of the liver. As can be expected oval cells started to multiply at 5 and 10 days after damage. Oval cell proliferation was observed by PCNA antigen expression using immunohistochemistry.

Specifically in the oval cells, an increase in beta-catenin protein, as well as Frezzled-2 was seen. Hepatocytes expressed upregulated Wnt-1.

In order to assess whether upregulation of Wnt pathway was an effect of oval cell proliferation or whether it was strictly necessary for this, the investigators induced oval cell proliferation in conditional knockouts of beta-catenin. In this scenario oval cell proliferation was inhibited.

There are numerous patents covering modulation of the beta-catenin pathway. For example, patent # 6,465,249 covers A method for in vitro self-renewal of mammalian stem cells, the method comprising: transfecting said stem cells in an in vitro culture medium with an exogenous nucleic acid comprising stabilized mutant .beta.-catenin coding sequences operably linked to a promoter. It will be interesting to see whether these types of approaches will be applied to generating or expanding hepatocytes useful for treatment of liver failure.