Systems-Level Analysis of Stem Cells in the Larval Stage of the Human Parasitic Flatworm Schistosoma

Abstract

This study combines quantitative biophysical approaches and functional genomic analysis to understand stem cell development in the human parasite Schistosoma mansoni. We anticipate these parasites will become a unique model system in which studies of fundamental stem cell biology have the potential to impact a devastating human disease. Schistosoma flatworms parasitize over 230 million people worldwide, causing schistosomiasis, a neglected tropical disease with a global socioeconomic burden nearly equivalent to that of HIV/AIDS and malaria. In addition to their relevance to human health, the complex biology of these parasites has fascinated scientists for nearly a century. Schistosomes transmit via a complex life cycle that alternates between obligate parasitism of snail intermediate and human definitive hosts. To facilitate these transitions, schistosomes develop sequentially four distinct body plans, a process accomplished by a population of stem cells that undergo multiple rounds of stage-specific self-renewal and differentiation. Here, we focus on the development of sporocysts (larval schistosomes) upon entry into snail hosts. At this stage, stem cells divide and asexually produce many simultaneously developing daughter embryos, leading to a geometric expansion of single sporocysts to thousands of infectious cercariae. Since little is known about the biology of these stem cells, we are developing novel fluorescence imaging methods to reconstruct the trajectories of these cells during development. We are integrating these studies with genome-wide analyses of gene expression and function. Our studies show that these cells resemble pluripotent stem cells called neoblasts, that drive long-term tissue homeostasis and regeneration in long-lived free-living flatworms. Functionally, we identify a group of evolutionarily conserved post-transcriptional regulators which maintain the enormous reproductive capacity of these cells.