Tapeworm stem cells as drivers of regeneration and reproduction

Abstract Parasitic flatworms, such as tapeworms, have global reach and cause a wide variety of symptoms from intestinal distress and lethargy to organ failure, seizures, and even death. These parasites have complex life cycles and a remarkable capacity for growth, reproduction, regeneration, and longevity. These physiological traits are enabled by stem cells, thus understanding stem cell behaviors and regulation in these parasites has the capacity to uncover a broad range of potential targets that can be exploited for future drug development. My foundational work establishing the rat tapeworm, Hymenolepis diminuta, as a tractable modern model organism and my initial characterization of stem cells and regeneration in this system make it ideal for this study. My goal is to elucidate stem cell-driven regeneration and reproduction in this tapeworm. I seek to discover the signals that regulate stem cell potency and enable regeneration of tapeworm proglottids, which are each a functional reproductive unit. To this end, I will identify subpopulations of stem cells and functionally assay for pluripotent potential using innovative cell isolation and transplantation methodologies. I have previously shown that microenvironmental signals that regulate regenerative ability are anteriorly biased. Thus, I will undertake high- throughput gene expression screening and RNA interference by targeting factors that are polarized along the anterior-posterior axis across the regeneration-competent tapeworm neck. Furthermore, I will functionally identify genetic regulators of the germline lineage and investigate the potential plasticity of germ cells, as well as their coordination with mechanisms that govern proglottid regeneration. These innovative studies exploit the natural progression of parasite development to make genetic discoveries and take a stem cell-centric approach to illuminate parasite biology. This is significant as I will be able to make fundamental discoveries in both stem and germ cell biology, as well as in a greater disease-relevant context.