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Drosophila adult midgut intestinal stem cells (ISCs) maintain tissue homeostasis by producing progeny that replace dying enterocytes and enteroendocrine cells. ISCs adjust their rates of proliferation in response to enterocyte turnover through a positive feedback loop initiated by secreted enterocyte-derived ligands. However, less is known about whether ISC proliferation is affected by growth of the progeny as they differentiate. Here we show that nutrient deprivation and reduced insulin signaling results in production of growth-delayed enterocytes and prolonged contact between ISCs and newly formed daughters. Premature disruption of cell contact between ISCs and their progeny leads to increased ISC proliferation and rescues proliferation defects in insulin receptor mutants and nutrient-deprived animals. These results suggest that ISCs can indirectly sense changes in nutrient and insulin levels through contact with their daughters and reveal a mechanism that could link physiological changes in tissue growth to stem cell proliferation.cadherin | cell adhesion | nutrition S elf-renewing stem cells respond to perturbations in tissue homeostasis by adjusting their rate of proliferation or by altering their total number (1). Although much is known about the mechanism of stem cell self-renewal (2), less is known about how stem cells sense and respond to these perturbations.The Drosophila adult midgut contains multipotent intestinal stem cells (ISCs) that divide once a day and generate daughters, known as enteroblasts, which then differentiate without dividing into either enteroendocrine cells or polyploid enterocytes ( Fig. S1A) (3, 4). Injury to the adult midgut results in acute loss of enterocytes and release of JAK-STAT and Egfr ligands by dying cells. These ligands directly activate the JAK-STAT and the Egfr-signaling pathways in ISCs (5-17), which results in an increased rate of ISC proliferation and enterocyte production, thereby linking the death of differentiated cells to a response that restores tissue homeostasis.Although regulation of ISC proliferation by enterocyte turnover is well understood, it remains unclear whether growth and differentiation of stem cell daughters can regulate ISC proliferation. In Drosophila, cell growth is dependent on nutrition and insulin signaling (18,19), and these physiological variables might also regulate ISC proliferation and growth of ISC daughters. Indeed, homeostatic mechanisms involving nutrition, insulin signaling, and stem cells have been characterized in the Drosophila ovary and testis, where germline and somatic stem cells respond to changes in the nutritional availability for gametogenesis by adjusting their rates of proliferation (20)(21)(22)(23)(24). Recently, it has been shown that the rate of ISC proliferation in both the Periplaneta americana and Drosophila midgut changes in response to dietary manipulations and insulin signaling (17,(25)(26)(27). However, the cell types mediating this response are not known. We show that enteroblasts nonautonomously regulate I...

Summary Organ fitness depends on appropriate maintenance of stem cell populations, and aberrations in functional stem cell numbers are associated with malignancies and aging. Symmetrical division is the best characterized mechanism of stem cell replacement, but other mechanisms could also be deployed, particularly in situations of high stress. Here, we show that after severe depletion, intestinal stem cells (ISCs) in the Drosophila midgut are replaced by spindle-independent ploidy reduction of cells in the enterocyte-lineage through a process known as amitosis. Amitosis is also induced by the functional loss of ISCs coupled with tissue demand and in aging flies, underscoring the generality of this mechanism. However, we also found that random homologous chromosome segregation during ploidy reduction can expose deleterious mutations through loss of heterozygosity. Together, our results highlight amitosis as an unappreciated mechanism for restoring stem cell homeostasis, but one with some associated risk in animals carrying mutations.

Maintenance of tissue homeostasis is critical in tissues with high turnover such as the intestinal epithelium. The intestinal epithelium is under constant cellular assault due to its digestive functions and its function as a barrier to chemical and bacterial insults. The resulting high rate of cellular turnover necessitates highly controlled mechanisms of regeneration to maintain the integrity of the tissue over the lifetime of the organism. Transient increase in stem cell proliferation is a commonly used and elaborate mechanism to ensure fast and efficient repair of the gut. However, tissue repair is not limited to regulating ISC proliferation, as emerging evidence demonstrates that the Drosophila intestine uses multiple strategies to ensure proper tissue homeostasis that may also extend to other tissues.

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