The Drosophila midgut is maintained throughout its length by superficially similar, multipotent intestinal stem cells that generate new enterocytes and enteroendocrine cells in response to tissue requirements. We found that the midgut shows striking regional differentiation along its anterior-posterior axis. At least ten distinct subregions differ in cell morphology, physiology and the expression of hundreds of genes with likely tissue functions. Stem cells also vary regionally in behavior and gene expression, suggesting that they contribute to midgut sub-specialization. Clonal analyses showed that stem cells generate progeny located outside their own subregion at only one of six borders tested, suggesting that midgut subregions resemble cellular compartments involved in tissue development. Tumors generated by disrupting Notch signaling arose preferentially in three subregions and tumor cells also appeared to respect regional borders. Thus, apparently similar intestinal stem cells differ regionally in cell production, gene expression and in the ability to spawn tumors.
Many cells in the body accumulate wear and tear over time, and a fraction of them are always nearing the end of their lives. However, in some tissues there are stem cells that can divide into daughter cells which then differentiate and replace the damaged cells. Unlike embryonic stem cells, these ‘adult tissue stem cells’ normally differentiate into only a few related cell types, but their ability to produce replacement cells keeps the tissue functioning normally. Here, Marianes and Spradling have investigated a type of adult stem cell, known as intestinal stem cells, that resides in the midgut of fruit flies.
The midgut is the major site of digestion in fruit flies, and functions much like the small intestine in mammals. This tissue is a long tube that is lined with two types of cells: digestive cells and hormone-producing cells. These cell types are maintained by thousands of apparently similar intestinal stem cells, and it has long been thought that the stem cells give rise to cells throughout the midgut by responding to the same set of signals. However, certain digestive processes—such as the breakdown or uptake of particular nutrients—are known to occur only in a specific portion of the intestine. For example, in fruit flies, a region in the middle of the intestine is acidified, and may act like an extra stomach. And in both fruit flies and mammals, iron is taken up mostly in the area of the gut just after the stomach. These regional differences in function have led to uncertainty over how midgut cells both arise and are replaced.
Marianes and Spradling now show, based on a detailed study of tissue cells and stem cells, that the midgut contains at least ten subregions that occur in a specific order. The cells in these subregions have distinct features, including shape, size and contents (e.g., stores of carbohydrates or nutrients). Each subregion appears to perform specific functions during digestion, and the cells in these subregions also transcribe genes that reflect their roles in breaking down or storing various nutrients. Interestingly, the stem cells in most subregions are distinct, and do not differentiate into the cells from adjacent subregions. The subregions also differ in their incidence of cancer: when a particular signal was inhibited in stem cells in all ten subregions, aggressive tumors formed in only three subregions and the tumor cells did not cross into neighboring subregions.
These observations may inform future studies of the mammalian small intestine and improve our understanding of its susceptibility to cancer and other diseases.