Dissecting the impact of Frizzled receptors in Wnt/β-catenin signaling of human mesenchymal stem cells

Wnt/β-catenin signaling is of fundamental importance in the
regulation of self-renewal, migration/invasion, and differentiation
of human mesenchymal stem cells (hMSCs). Because little information
is available about the function of Frizzled receptors (Fzds) as the
main receptors of Wnt proteins in hMSCs, we first performed
comparative Fzd mRNA expression profiling. Fzd9 and Fzd10 were not
expressed in hMSCs. While Fzd3 was expressed at low levels in
hMSCs, the other Fzds exhibited high expression rates. Activation
and repression of Wnt signaling in hMSCs revealed that the
expression levels of Fzd1, Fzd6, and Fzd7 are positively correlated
with the Wnt/β-catenin activation status, whereas Fzd8 exhibited an
inverse relation. For studying the functional relevance of Fzds in
Wnt/β-catenin signaling, RNA interference, ectopic expression
studies, and rescue approaches were performed in hMSCs carrying a
highly sensitive TCF/LEF reporter gene system (Gaussia luciferase).
We found that, Fzd1, Fzd5, Fzd7, and Fzd8 are largely involved in
Wnt/β-catenin signaling of hMSCs. Moreover, the knockdown of Fzd5
can be compensated by the ectopic expression of Fzd7. Conversely,
the ectopic expression of Fzd5 in Fzd7-knockdown hMSCs resulted in
a rescue of Wnt/β-catenin signaling, pointing to a functional
redundancy of Fzd5 and Fzd7.