Study reveals stem cells in a human parasite

From the point of view of its ultimate (human) host, the parasitic flatworm Schistosoma mansoni has a gruesome way of life.

It hatches in feces-tainted water, grows into a larva in the body of a snail and then burrows through human skin to take up residence in the veins. Once there, it grows into an adult, mates and, if it’s female, starts laying eggs. It can remain in the body for decades.

A new study offers insight into the cellular operations that give this flatworm its extraordinary staying power. The researchers, from the University of Illinois, demonstrated for the first time that S. mansoni harbors adult, non-sexual stem cells that can migrate to various parts of its body and replenish tissues. Their report appears in the journal Nature.

According to the World Health Organization, more than 230 million people are in need of treatment for Schistosoma infections every year. Most live in impoverished areas with little or no access to clean water. Infection with the worm (also known as a blood fluke) can lead to damaging inflammation spurred by the presence of the worm’s eggs in human organs and tissues.

“The female lays eggs more or less continuously, on the order of hundreds of eggs per day,” said U. of I. cell and developmental biology professor and Howard Hughes Medical Institute Investigator Phillip Newmark, who led the study with postdoctoral researcher James J. Collins III.

“The eggs that don’t get excreted in the feces to continue the life cycle actually become embedded inside host tissues, typically the liver, and those eggs trigger a massive inflammatory response that leads to tissue damage.”

Children are especially vulnerable to the effects of infection, in some cases experiencing delays in growth and brain development as a result of chronic inflammation brought on by the parasites.

The new study began with an insight stemming from years of work on a different flatworm, the planarian, in Newmark’s lab. Collins thought that schistosomes might make use of the same kinds of stem cells (called neoblasts in planarians) that allow planarians to regenerate new body parts and organs from even tiny fragments of living tissue.

“It just stood to reason that since schistosomes, like planaria, live so long that they must have a comparable type of system,” Collins said. “And since these flatworms are related, it made sense that they would have similar types of cells. But it had never been shown.”

In a series of experiments, Collins found that the schistosomes were loaded with proliferating cells that looked and behaved like planarian neoblasts, the cells that give them their amazing powers of regeneration. Like neoblasts, the undifferentiated cells in the schistosomes lived in the mesenchyme, a kind of loose connective tissue that surrounds the organs. And like neoblasts, these cells duplicated their DNA and divided to form two “daughter” cells, one of which copied its DNA again, a process that normally precedes cell division.

“Stem cells do two things,” Newmark said. “They divide to make more stem cells and they give rise to cells that can differentiate.”

Collins had labeled the cells with fluorescent markers. This allowed him to watch how they behaved. He noted that over the course of a few days, some of the labeled cells migrated into the gut or muscle, to become part of those tissues.

“We label the cells when they’re born and then we see what they grow up to become,” Collins said. “This is not conclusive evidence that these cells are equivalent to the planarian neoblasts, but it is consistent with the hypothesis that they are.”

The researchers went deeper, determining which genes were turned on or off, up or down in the proliferating cells as compared with the non-dividing cells. They identified a gene in the proliferating cells that coded for a growth factor receptor very similar to one found in planarians. When the researchers switched off the parasite’s ability to make use of this gene (using a technique called RNA interference in worms grown in the lab), the proliferating cells gradually died out.

“We postulated that these cells are important for the longevity of the parasite,” Collins said. “Now we can start asking which genes regulate these cells.”

“We started with the big question: How does a simple parasite survive in a host for decades?” Newmark said. “That implies that it has ways of repairing and maintaining its tissues. This study gives us insight into the really interesting biology of these parasites, and it may also open up new doors for making that life cycle a lot shorter.”