Moving Toward Regeneration

Photo: Planarian stem cells

After transplantation of healthy
tissue and subsequent decapitation,
planarian stem cells leave the graft
and migrate towards the amputation
site while proliferating and producing
progeny. This wound-induced migration
rescues the lethally irradiated host
animal and eventually the stem cell
compartment is completely repopulated with
fully functional stem cells (shown in blue);
© Dr. Otto C. Guedelhoefer, IV, University
of California, Berkeley

The skin, the blood, and the lining of the gut—adult stem cells replenish them daily. But stem cells really show off their healing powers in planarians, humble flatworms fabled for their ability to rebuild any missing body part. Just how adult stem cells build the right tissues at the right times and places has remained largely unanswered.

Now researchers at the Stowers Institute for Medical Research describe a novel system that allowed them to track stem cells in the flatworm Schmidtea mediterranea. The team found that the worms' stem cells, known as neoblasts, march out, multiply, and start rebuilding tissues lost to amputation.

"We were able to demonstrate that fully potent stem cells can mobilize when tissues undergo structural damage," says Doctor Alejandro Sánchez Alvarado, who led the study. "And these processes are probably happening to both you and me as we speak, but are very difficult to visualize in organisms like us."

Stem cells hold the potential to provide an unlimited source of specialized cells for regenerative therapy of a wide variety of diseases but delivering human stem cell therapies to the right location in the body remains a major challenge. The ability to follow individual neoblasts opens the door to uncovering the molecular cues that help planarian stem cells navigate to the site of injury and ultimately may allow scientists to provide therapeutic stem cells with guideposts to their correct destination.

"Human counterparts exist for most of the genes that we have found to regulate the activities of planarian stem cells," says Sánchez Alvarado. "But human beings have these confounding levels of complexity. Planarians are much simpler making them ideal model systems to study regeneration."

Scientists had first hypothesized in the late 1800s that planarian stem cells, which normally gather near the worms' midlines, can travel toward wounds. The past century produced evidence both for and against the idea. Sánchez Alvarado, armed with modern tools, decided to revisit the question.

For the new study, first author Doctor Otto C. Guedelhoefer exposed S. mediterranea to radiation, which killed the worms' neoblasts while leaving other types of cells unharmed. The irradiated worms would wither and die within weeks unless Guedelhoefer transplanted some stem cells from another worm. The graft's stem cells sensed the presence of a wound—the transplant site—migrated out of the graft, reproduced and rescued their host. Unlike adult stem cells in humans and other mammals, planarian stem cells remain pluripotent in fully mature animals and remain so even as they migrate.

But when he irradiated only a part of the worm's body, the surviving stem cells could not sense the injury and did not mobilize to fix the damage, which showed that the stem cells normally stay in place. Only when a fair amount of irradiated tissue died did the stem cells migrate to the injured site and start to rebuild. Next, Guedelhoefer irradiated a worm's body part and cut it with a blade. The surviving stem cells arrived at the scene within days.

But Guedelhoefer went further. He pinpointed the locations of stem cells and studied how far they dispersed using RNA whole-mount in situ hybridization (WISH), specifically adapted to planarians in Sánchez Alvarado's lab. Using WISH, he observed both original stem cells and their progeny by tagging specific pieces of mRNA . The technique allowed him to determine that pluripotent stem cells can travel and produce different types of progeny at the same time.

"In other systems, most migrating stem cell progeny are not pluripotent," says Guedelhoefer. "For the most part, blood stem cells in humans stay in the bone marrow but their progeny leave and turn into a few other cell types." But in planarians, it looks like those two things are completely separate. Stem cells can move and maintain the full potential to turn into other types of cells."; Source: Stowers Institute for Medical Research