Using planarian flatworms to understand organ regeneration

How animals repair their internal organs after injury is not well understood. Planarian flatworms are useful models for studying this question. After injury, they are able to re-grow missing body parts, as well as all as organs that are damaged or lost, such as brain, eyes, and intestine.

Injury initiates a complex set of cellular events. In planarians, specialized somatic stem cells called neoblasts divide and give rise to all of the different cell types required to rebuild fully functional body parts. Old tissue remaining after amputation remodels and integrates with the new cells that are produced.

The molecular signaling pathways coordinating these cellular behaviors to achieve organ regeneration have not been well characterized. David Forsthoefel, a postdoctoral researcher in Newmark's laboratory and the lead author on the study, wanted to address the problem using the planarian intestine as a "model organ," in part because so few animals are capable of repairing severe damage to their digestive systems.

"The ability to recover from loss of digestive tissue is rare in the animal kingdom," Forsthoefel said. "What we learn from how a simple worm deals with gut damage might one day help us to come up with better medical therapies, for example in the treatment of short bowel syndrome, in which segments of intestine must be removed from patients with digestive diseases, leading to impaired nutrient absorption."

Forsthoefel developed a method for purifying a single intestinal cell type from the planarian gut. He and Newmark lab members then went on to identify over a thousand genes that were uniquely expressed at higher levels in intestinal cells than in the surrounding planarian tissues. Guessing that some of these genes would have important roles during intestinal growth and regeneration, they probed the function of a subset of these genes using a technique called RNA interference, in which the expression of individual genes is selectively inhibited. They were able to pinpoint functions for specific genes, for example in the establishment of the appropriate pattern of intestinal branches, and the production of functional intestinal cells capable of taking up nutrients.

The authors also identified a transcription factor called nkx-2.2 that, although expressed in the intestine, was required for neoblasts to proliferate in various contexts, including after injury. This result suggests a potential role for the intestine in regulating stem cell division, a result Forsthoefel is following up by identifying genes downstream of Nkx-2.2 that might have more direct roles in communication between the intestine and neoblasts.

"How cells in the vicinity of damaged tissue contribute to the choices stem cells make in response to injury is an area of regeneration biology where much more research is needed," Forsthoefel said.

The field of regeneration research is rife with such uncharted territory. How do animals manage to produce the correct number specific cell types, at the correct locations? What are the signals that instruct stem cells to become specific cell types, and where do they come from? How is organ-specific morphology, for example the number of intestinal branches, determined? This study from the Newmark lab, the first systematic effort to elucidate intestinal morphogenesis in planarians, lays the groundwork for addressing many of these fundamental questions of organ regeneration.