Planarian EGF repeat-containing genes megf6 and hemicentin are required to restrict the stem cell compartment

The extracellular matrix (ECM) is important for maintaining the boundaries between tissues. This role is particularly critical in the stem cell niche, as pre-neoplastic or cancerous stem cells must pass these boundaries in order to invade into the surrounding tissue. Here, we examine the role of the ECM as a regulator of the stem cell compartment in the planarian Schmidtea mediterranea, a highly regenerative, long-lived organism with a large population of adult stem cells. We identify two EGF repeat-containing genes, megf6 and hemicentin, with identical knockdown phenotypes. We find that megf6 and hemicentin are needed to maintain the structure of the basal lamina, and in the absence of either gene, pluripotent stem cells migrate ectopically outside of their compartment and hyper-proliferate, causing lesions in the body wall muscle. These muscle lesions and ectopic stem cells are also associated with ectopic gut branches, which protrude from the normal gut towards the dorsal side of the animal. Interestingly, both megf6 and hemicentin knockdown worms are capable of regenerating tissue free of both muscle lesions and ectopic cells, indicating that these genes are dispensable for regeneration. These results provide insight into the role of planarian ECM in restricting the stem cell compartment, and suggest that signals within the compartment may act to suppress stem cell hyperproliferation. Author summary The freshwater planarian maintains a large population of adult stem cells throughout its long lifespan. Although these stem cells are constantly dividing, the rate of division is tightly controlled to such a degree that planarians almost never develop neoplastic growths. In addition, the stem cells are located in a specific spatial compartment within the animal, although no known physical boundary keeps them in place. What mechanisms do planarians use to control the number, rate of division, and location of their stem cells? Here, we find that two EGF repeat-containing genes, megf6 and hemicentin, are required to keep stem cells within their compartment. Although these two genes are expressed in different cell populations, we find that both are required to maintain the epithelial basal lamina. In the absence of either gene, stem cells can escape their compartment and migrate towards the skin of the animal, where they divide at an accelerated rate and cause lesions in the muscle. These results show that the extracellular matrix plays a role in limiting the boundaries of the stem cell compartment.