The Hippo pathway regulates Echinococcus stem cell function

Abstract text

Introduction: Alveolar echinococcosis (AE) is a lethal zoonosis prevalent in the Northern Hemisphere and is caused by the metacestode larva of the fox tapeworm Echinococcus multilocularis. Growth of the Echinococcus metacestode within host organs is stem cell driven and almost unrestricted, leading to massive tumorous lesions. Organ size in metazoans is typically regulated by the Hippo pathway, the contribution of which to Echinococcus development has so far not been addressed. Objectives: To characterize EchinococcusHippo signaling components and their contribution to parasite development. Materials & methods: We used bioinformatics to identify Echinococcus Hippo pathway components and in vitro cultivation systems, combined with inhibitor assays were used to study their role in Echinococcus proliferation and growth. Results: We identified Echinococcus orthologs of the kinases Hippo and Warts, the regulatory proteins Salvador and Mats, the co-activator Yorkie and the transcription factor Scalloped which are all expressed by differentiated cells and by stem cells in Echinococcus larvae. By applying the known Hippo inhibitors TRULI and XMU-MP-1 to metacestode vesicles and protoscoleces, we observed significant effects on larval morphology indicating alterations in stem cell proliferation. Particularly, XMU-MP-1 induced "giant" stem cells in metacestode vesicles, indicating direct influences of Hippo signaling on parasite mitosis. Furthermore, we show that RNAi knockdown of Echinoccocus yorkie induces vesicle formation by stem cells. Conclusions: Our data indicate that a complete Hippo-signaling pathway is present in E. multilocularis and contributes to proliferation dynamics of germinative stem cells, which are the decisive cell type in parasite growth within the host. Our data are relevant for understanding Echinococcus stem cell based developmental processes and may be exploited for the development of novel anti-parasitics.