Research Article: Tissue Degeneration following Loss of Schistosoma mansoni cbp1 Is Associated with Increased Stem Cell Proliferation and Parasite Death In Vivo

Date Published: November 3, 2016

Publisher: Public Library of Science

Author(s): Julie N. R. Collins, James J. Collins, Matty Knight.


Schistosomiasis is second only to malaria in terms of the global impact among diseases caused by parasites. A striking feature of schistosomes are their ability to thrive in their hosts for decades. We have previously demonstrated that stem cells, called neoblasts, promote homeostatic tissue maintenance in adult schistosomes and suggested these cells likely contribute to parasite longevity. Whether these schistosome neoblasts have functions independent of homeostatic tissue maintenance, for example in processes such as tissue regeneration following injury, remains unexplored. Here we characterize the schistosome CBP/p300 homolog, Sm-cbp1. We found that depleting cbp1 transcript levels with RNA interference (RNAi) resulted in increased neoblast proliferation and cell death, eventually leading to organ degeneration. Based on these observations we speculated this increased rate of neoblast proliferation may be a response to mitigate tissue damage due to increased cell death. Therefore, we tested if mechanical injury was sufficient to stimulate neoblast proliferation. We found that mechanical injury induced both cell death and neoblast proliferation at wound sites, suggesting that schistosome neoblasts are capable of mounting proliferative responses to injury. Furthermore, we observed that the health of cbp1(RNAi) parasites progressively declined during the course of our in vitro experiments. To determine the fate of cbp1(RNAi) parasites in the context of a mammalian host, we coupled RNAi with an established technique to transplant schistosomes into the mesenteric veins of uninfected mice. We found transplanted cbp1(RNAi) parasites were cleared from vasculature of recipient mice and were incapable of inducing measurable pathology in their recipient hosts. Together our data suggest that injury is sufficient to induce neoblast proliferation and that cbp1 is essential for parasite survival in vivo. These studies present a new methodology to study schistosome gene function in vivo and highlight a potential role for schistosome neoblasts in promoting tissue repair following injury.

Partial Text

Schistosomes infect over 200 million people and are a major cause of morbidity in the developing world. The primary driver of this morbidity is the prodigious egg production of these parasites, which can lay several hundred eggs every day while living in the vasculature of their hosts [1]. A large fraction of these eggs are swept into the circulation and become lodged in host organs (such as the liver and bladder), leading to inflammatory responses that can compromise organ function [2]. The pathological consequences of schistosome egg production are compounded by the fact that schistosomes can survive and produce eggs for decades inside their human hosts [1, 3]. Understanding the developmental forces that promote parasite longevity is essential for understanding the chronic nature of this disease.

Aside from supporting new cell birth during the physiological turnover of tissues (e.g., the tegument [5]), we know relatively little about the roles that neoblasts play in the biology of adult schistosomes. Here, we report that reductions in cbp1 levels result in simultaneous elevations of both cell proliferation and cell death. The esophageal glands were emblematic of this: apoptosis driven cell death was accompanied by massive accumulations of proliferative neoblasts. These observations suggested that neoblasts might be equipped to respond to lost or damaged tissues, an observation we confirmed by demonstrating that physical wounding induced proliferative neoblasts to accumulate around wound sites. Based on these data we suggest a model in which reduction of cbp1 levels leads to cell death and tissue loss throughout the parasite (Fig 6). This cell loss is (directly or indirectly) sensed by neoblasts resulting in an increased rate of neoblast proliferation. Since we observe large increases in the number of cells expressing the neoblast progeny marker tsp-2, it is likely the neoblasts then differentiate to restore lost cells. Because cbp1 levels remain depressed due to the effects of RNAi these newly differentiated cells die, inducing more neoblast proliferation. Tissue degeneration and the inability of neoblasts to restore tissue function eventually results in parasite death.




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