Adult somatic stem cells in the human parasite Schistosoma mansoni

Howard Hughes Medical Institute and Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Nature (Impact Factor: 41.46). 02/2013; 494(7438):476-9. DOI: 10.1038/nature11924
Source: PubMed


Schistosomiasis is among the most prevalent human parasitic diseases, affecting more than 200 million people worldwide. The aetiological agents of this disease are trematode flatworms (Schistosoma) that live and lay eggs within the vasculature of the host. These eggs lodge in host tissues, causing inflammatory responses that are the primary cause of morbidity. Because these parasites can live and reproduce within human hosts for decades, elucidating the mechanisms that promote their longevity is of fundamental importance. Although adult pluripotent stem cells, called neoblasts, drive long-term homeostatic tissue maintenance in long-lived free-living flatworms (for example, planarians), and neoblast-like cells have been described in some parasitic tapeworms, little is known about whether similar cell types exist in any trematode species. Here we describe a population of neoblast-like cells in the trematode Schistosoma mansoni. These cells resemble planarian neoblasts morphologically and share their ability to proliferate and differentiate into derivatives of multiple germ layers. Capitalizing on available genomic resources and RNA-seq-based gene expression profiling, we find that these schistosome neoblast-like cells express a fibroblast growth factor receptor orthologue. Using RNA interference we demonstrate that this gene is required for the maintenance of these neoblast-like cells. Our observations indicate that adaptation of developmental strategies shared by free-living ancestors to modern-day schistosomes probably contributed to the success of these animals as long-lived obligate parasites. We expect that future studies deciphering the function of these neoblast-like cells will have important implications for understanding the biology of these devastating parasites.

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Available from: Phillip A Newmark, Aug 14, 2014
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    • "Because FGFR-B expression was also detected in the gastrodermis it seems to be conclusive that the inhibitor had a direct effect on this tissue. Furthermore, it seems likely that these alterations were triggered by a targeting of FGFR-signaling in PSCs, since it has been suggested by Collins et al. (2013) that gastrodermis renewal depends on PSC activity. Besides this, inhibitor treatment also affected the gonads, which contained damaged cells. "
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    ABSTRACT: In the search for new strategies to fight schistosomiasis, the unique reproductive biology of Schistosoma mansoni has come into the focus of research. The development of the gonads and the ability of egg production are fundamental not only for continuing the life cycle but also for pathogenicity. Previous studies of schistosome biology demonstrated an influence of pairing on gonad development of the female and on gene expression profiles in both genders. Due to the limited access to specific tissues, however, most of these studies were done at the level of whole worms neglecting individual tissues that may be targets of pairing-dependent processes. Recently, we established a protocol allowing the isolation of testes and ovaries from adult S. mansoni. Here, we describe tissue-specific qRT-PCR analyses comparing transcript levels of selected genes on the basis of RNA from gonads and whole worms. Gene expression in ovary and testes was in some cases found to be significantly influenced by pairing, which was not traceable in whole worms. Among the candidate genes identified as regulated by pairing in gonads were the frizzled homolog SmFz1 and the two fibroblast growth factor receptor homologs SmFGFR-A and SmFGFR-B. First functional characterizations were done, including comparative qRT-PCR analyses, in situ-localization experiments, heterologous expression in Xenopus oocytes (SmFGFR-A/B), and inhibitor studies using the Fz/Dvl-pathway inhibitor 3289-8625, or BIBF1120 blocking FGFR-signaling. Besides confirming gonad localization and receptor functions, inhibitor-induced phenotypes were observed in vitro such as decreased egg production as well as drastic effects on gonad differentiation, morphology, embryogenesis, and survival of adult worms. In summary, these results emphasise the usefulness of tissue-specific qRT-PCRs for selection of candidate genes with important roles in reproduction, allowing subsequent studies to determine their suitability as drug targets.
    Frontiers in Genetics 06/2014; 5:170. DOI:10.3389/fgene.2014.00170
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    • "As a possible general marker of all proliferating germinative cells, we analyzed the expression of histone H2B homologs, since canonical histones are synthesized in a cell-cycle dependent manner: histone transcripts only accumulate during the S-phase, when new histones are needed to accompany the synthesis of DNA [60]. Furthermore, H2B genes have been found to be specifically expressed in proliferating planarian neoblasts and in the neoblast-like cells of the trematode Schistosoma mansoni[61,62]. "
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    ABSTRACT: It is believed that in tapeworms a separate population of undifferentiated cells, the germinative cells, is the only source of cell proliferation throughout the life cycle (similar to the neoblasts of free living flatworms). In Echinococcus multilocularis, the metacestode larval stage has a unique development, growing continuously like a mass of vesicles that infiltrate the tissues of the intermediate host, generating multiple protoscoleces by asexual budding. This unique proliferation potential indicates the existence of stem cells that are totipotent and have the ability for extensive self-renewal. We show that only the germinative cells proliferate in the larval vesicles and in primary cell cultures that undergo complete vesicle regeneration, by using a combination of morphological criteria and by developing molecular markers of differentiated cell types. The germinative cells are homogeneous in morphology but heterogeneous at the molecular level, since only sub-populations express homologs of the post-transcriptional regulators nanos and argonaute. Important differences are observed between the expression patterns of selected neoblast marker genes of other flatworms and the E. multilocularis germinative cells, including widespread expression in E. multilocularis of some genes that are neoblast-specific in planarians. Hydroxyurea treatment results in the depletion of germinative cells in larval vesicles, and after recovery following hydroxyurea treatment, surviving proliferating cells grow as patches that suggest extensive self-renewal potential for individual germinative cells. In E. multilocularis metacestodes, the germinative cells are the only proliferating cells, presumably driving the continuous growth of the larval vesicles. However, the existence of sub-populations of the germinative cells is strongly supported by our data. Although the germinative cells are very similar to the neoblasts of other flatworms in function and in undifferentiated morphology, their unique gene expression pattern and the evolutionary loss of conserved stem cells regulators suggest that important differences in their physiology exist, which could be related to the unique biology of E. multilocularis larvae.
    EvoDevo 03/2014; 5(1):10. DOI:10.1186/2041-9139-5-10 · 3.03 Impact Factor
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    • "Wang, Collins and Newmark have now characterized the germinal cell population by profiling gene expression in the cells, validating these findings with fluorescence in situ hybridization, and then using RNA interference to silence individual genes in order to determine their functions. Their results uncovered similarities, at both the molecular and functional level, between these germinal cells and stem cells that have recently been identified in adult parasites (Collins et al., 2013). There were also similarities with pluripotent stem cells known as neoblasts found in non-parasitic free-living flatworms (planarians), and with cells that produce gametes in other multicellular animals. "
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    ABSTRACT: Learning more about the cells that enable parasitic worms called schistosomes to reproduce inside snails could lead to new treatments that prevent these parasites from being transmitted to humans.
    eLife Sciences 07/2013; 2:e01115. DOI:10.7554/eLife.01115 · 9.32 Impact Factor
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