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GEN News Highlights : Jan 14, 2014

Revving the Stem Cell Engine

Like a car idling, not moving in any direction but ready to roll, stem cells may remain in their undifferentiated state, rumblingly pluripotent, and ready to become any type of mature cell. Pluripotent stem cells appear to have their engines tuned via Wnt signaling. But which Wnts and Wnt receptors are involved? Only recently, thanks to the work of researchers at the University of California, San Diego (UC-San Diego), have such details emerged.

These researchers investigated the role of the highly conserved Wnt signaling pathway in controlling the self-renewal of human embryonic stem cells (ESCs). They found that the Wnt receptor encoded by the frizzled family receptor 7 (FZD7) gene is essential for maintaining human ESCs in an undifferentiated and pluripotent state.

This finding appeared in an article published January 13 in the Proceedings of the National Academy of Sciences, in an article entitled “The Wnt receptor FZD7 is required for maintenance of the pluripotent state in human embryonic stem cells.” FZD7 is a so-called onco-fetal protein. It is expressed only during embryonic development and by certain human tumors.

“FZD7 expression is significantly elevated in undifferentiated cells relative to differentiated cell populations, and interfering with its expression or function, either by short hairpin RNA-mediated knockdown or with a fragment antigen binding (Fab) molecule directed against FZD7, disrupts the pluripotent state of hESCs,” the authors wrote. “The FZD7-specific Fab blocks signaling by Wnt3a protein by down-regulating FZD7 protein levels, suggesting that FZD7 transduces Wnt signals to activate Wnt/β-catenin signaling.”

Expressing the point more directly, principal investigator Karl Willert, Ph.D., assistant professor in the department of cellular and molecular medicine, added, “If we block FZD7 function, thus interfering with the Wnt pathway, hESCs exit their undifferentiated and pluripotent state.”

This discovery adds to the growing collection of cell surface molecules required for hESC self-renewal. These molecules include FGF, insulin-like growth factor, and epidermal growth factor receptors, E cadherin, and L1 cell adhesion molecule.

The article by Willert and colleagues also notes that other investigators have associated FZD7 expression with several types of cancer. “These studies,” they point out, “have led to significant interest in FZD7 as a cancer stem cell marker, the targeting of which may be of therapeutic value in the treatment of cancers in which Wnt signaling is deregulated.” They also add that the specific FZD7 binding protein (FZD7-Fab), which blocks FZD7 function, as well as Wnt3a signaling, may represent an effective method to disrupt Wnt-FZD7 signaling in cancer cells.

So, besides showing that FZD7 encodes a regulator of the pluripotent state and that hESCs require endogenous Wnt/β-catenin signaling through FZD7 to maintain an undifferentiated phenotype, the investigators have found a mechansm that may serve to “cut the throttle” on cancer.