Parasitology

Rejuvenation through stem cells

The discovery that schistosomes possess adult stem cells could explain the long-term persistence of these parasitic worms in humans. Targeting a protein produced by the cells might damage schistosome defences. See Letter p.476

Schistosomes are nasty. These multicellular parasitic worms infect more than 200 million individuals worldwide, living and laying eggs within their hosts' blood vessels. The eggs become trapped in major organs such as the liver and intestine, causing prolonged inflammatory reactions1. And despite aggressive immune responses by the infected host, the pathogens persist for 6–10 years on average, but sometimes for much longer. Such robustness strongly implies that schistosomes can replace or repair tissues that have been damaged through ageing or by host immune mechanisms, although how this occurs was unknown. On page 476 of this issue, Collins et al.2 lift the curtain on this mystery, reporting that schistosomes possess a widely distributed population of adult stem cells that can differentiate into many cell typesFootnote 1.

A close relative of schistosomes are the free-living planarians; the two groups are members of the phylum Platyhelminthes (flatworms). Planarians have exceptional regenerative powers and so have become valuable teaching tools and models for studying stem-cell biology. In these organisms, the only proliferating somatic (non-germ) cells are stem cells called neoblasts, which have a distinctive morphology and are destroyed by radiation.

Experts in studying planarians, Collins and colleagues focused on Schistosoma mansoni — a parasitic flatworm that is poorly understood and difficult to work with — to determine whether it too possesses adult stem cells. They discovered dividing cells that were lost on exposure to radiation and that resembled planarian neoblasts in appearance, localization and gene-expression profile. Remarkably, the cells could self-renew to sustain their own population numbers while simultaneously seeding daughter cells into new lineages, such as muscle and intestinal epithelium — truly stem-cell-like behaviour.

The authors also identified SmfgfrA, a gene that they found is preferentially expressed in S. mansoni adult stem cells and which encodes a receptor for the parasite's version of fibroblast growth factor (FGF; Fig. 1a). FGFs promote proliferation and maintain the 'stemness' of stem cells in other systems, most notably in cultures of human embryonic stem cells3. Following this lead, Collins et al. show that inhibiting SmfgfrA expression results in both loss of proliferating mesenchymal stem cells underlying the parasite's intestinal epithelium, and a reduction in the expression of gene transcripts normally found at high levels in neoblasts.

Figure 1: Schistosome survival strategies and life cycle.
figure1

a, Collins et al.2 have identified adult stem cells in the mesenchymal tissue of male schistosomes, which underlies the intestinal epithelium. These 'neoblasts' can self-renew through a process that may involve activation of the gene SmfgfrA, which encodes a FGF-receptor-like protein, SmfgfrA. They can also produce daughter cells capable of differentiating into multiple cell types, including muscle and intestinal epithelial cells. b, Schistosomes have a complex life cycle. In their mammalian host (humans or, in the laboratory, mice), they reproduce sexually, with the female parasite producing eggs. The eggs pass into the environment through the host's urine or faeces, eventually hatching to release larval stages that infect an intermediate host, the aquatic snail. It is in snails that the infectious larvae form, and they mature into adult parasites once they have entered their human host.

The discovery that FGF-receptor-mediated signalling is crucial for the maintenance of adult schistosome stem cells is noteworthy not just because it links stemness in organisms at opposite extremes of multicellular complexity— schistosomes and humans. It also suggests a potential means of interfering with this parasite's life cycle (Fig. 1b).

Treatment of schistosomiasis currently relies exclusively on the drug praziquantel, which is both safe and commonly available, especially thanks to funding from the Bill & Melinda Gates Foundation and Merck. However, the widespread availability and repetitive use of this drug, coupled with the fact that it often fails to clear infection completely, have led to concerns about the development of drug resistance4. Indeed, schistosomes can repair surface damage caused by subcurative doses of praziquantel, making the search for alternative treatments a priority. Because stem cells may have a crucial role in praziquantel resistance, it is appealing to envisage the development of drugs that inhibit SmfgfrA, or other genes essential for maintaining schistosomal adult stem cells, as adjuncts to existing therapy.

The list of intriguing questions that arise from this work is long. For instance, when do neoblasts form during schistosomal embryogenesis? What is their role in the various stages of the parasite's life cycle? And is the cells' ability to self-renew exhaustible under appropriate immune or metabolic pressure?

But perhaps the most tantalizing question is what is happening in female parasites. Schistosomes are unusual among Platyhelminthes in having two sexually distinct forms. Yet Collins and colleagues conducted their studies almost entirely on adult male organisms.

A remarkable feature of schistosome biology is that female parasites live enclosed within a specialized canal on the ventral surface of the male's body, and they rely on this niche to reach, and maintain, sexual maturity. The molecular basis for this reliance is unclear, but an organ called the vitellarium, which produces cells that are packaged into the egg with the fertilized ovum, is highly sensitive to the presence of the male; it shrinks to a vestigial form in females that have become separated from their partners.

Vitellarial tissues can regrow if females mate again, possibly owing to the presence of vitellarium-specific stem cells called S1 cells5. How S1 cells are related to the neoblast-like cells identified by Collins et al. is unknown, but is potentially addressable using the approaches pioneered by the authors' lab. Such studies would be exciting, as they promise to reveal how the vitellarium responds to the presence of the male parasite. Given that egg production by schistosomes is central to both the transmission of infection (Fig. 1) and the development of disease, elucidating this process may also have practical value.

Working from a baseline established in planarians, Collins et al. have taken full advantage of advances in our understanding of the schistosome genome6 and the development of reverse-genetics approaches in these organisms7. They have thereby made a highly informative and valuable cross-cultural foray from studying stem cells in free-living worms to studying them in parasitic worms2. Rejuvenating indeed!

Notes

  1. 1.

    *This article and the paper under discussion2 were published online on 20 February 2013.

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Correspondence to Edward J. Pearce.

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Pearce, E. Rejuvenation through stem cells. Nature 494, 438–439 (2013). https://doi.org/10.1038/nature11953

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