Somatic and germline fate decisions in dynamic stem cell utilization by tapeworms

About This Grant

Project Summary Growing evidence suggests that stem cells are crucial to the success and transmission of many helminths. As helminths cause a wide variety of symptoms from intestinal distress and lethargy to organ failure, seizures and even death, discoveries in helminth biology have the potential to lessen human and animal suffering. Tapeworms have enormous capacity to grow, regenerate and reproduce in a stem cell-dependent manner, but pathologically significant tapeworm species are extremely difficult to study in the laboratory. We have performed foundational work on establishing Hymenolepis diminuta (rat tapeworm) into a tractable and modern model organism. Our long-term goal is to use H. diminuta to elucidate the molecular regulation of stem cells with potential application to helminths in general. Previous work shows that H. diminuta is a prolific regenerator, but the ability to regenerate is confined to the most anterior tissue of the neck/germinative region (GR). As tapeworms can regenerate fully reproductive structures from this tissue, fundamental somatic and germline fate transitions must occur here. Intriguingly, we find that a known reproductive regulator in flatworms: nonribosomal peptide synthetase (nrps) is strongly expressed in a spatially distinct region toward the anterior GR. Together, these observations suggest that there is a level of spatial regulation of stem cells that we can leverage. Our central hypothesis is that heterogeneous stem cell subpopulations and their niches are spatially restricted in the GR of H. diminuta. We propose to describe the distribution of stem cell subpopulations within the GR and perform functional studies to ascertain how these subpopulation states/types are determined. Our work is innovative because it exploits biological features of H. diminuta in combination with state-of-the-art methods in spatial transcriptomics and cell transplantations to functionally interrogate this parasite in ways that are near impossible in other tapeworms. We will test our hypothesis using three specific aims: Aim 1) Identify spatially distinct subpopulations of somatic and germline stem cells, Aim 2) Functionally determine stem cell hierarchies in the regeneration- competent GR and Aim 3) Explore nrps+ cells as a putative stem cell/germ cell niche. The expected outcome is that we will successfully determine somatic, germline and potentially pluripotent stem cell states that are spatially segregated within the GR. We will also determine if nrps serves as a bona fide stem cell or germ cell niche. Our proposal is significant because the gaps in our knowledge of how all important soma-germline stem cell transitions are regulated means that we are blind to potential vulnerabilities of these parasite or points of robustness for their success. Elucidating these mechanisms will strengthen our arsenal to target parasitic helminths.