Abstract
Drosophila melanogaster larvae irradiated with doses of ionizing radiation (IR) that kill about half of the cells in larval imaginal discs still develop into viable adults. How surviving cells compensate for IR-induced cell death to produce organs of normal size and appearance remains an active area of investigation. We have identified a subpopulation of cells within the continuous epithelium of Drosophila larval wing discs that shows intrinsic resistance to IR- and drug-induced apoptosis. These cells reside in domains of high Wingless (Wg, Drosophila Wnt-1) and STAT92E (sole Drosophila signal transducer and activator of transcription [STAT] homolog) activity and would normally form the hinge in the adult fly. Resistance to IR-induced apoptosis requires STAT and Wg and is mediated by transcriptional repression of the pro-apoptotic gene reaper. Lineage tracing experiments show that, following irradiation, apoptosis-resistant cells lose their identity and translocate to areas of the wing disc that suffered abundant cell death. Our findings provide a new paradigm for regeneration in which it is unnecessary to invoke special damage-resistant cell types such as stem cells. Instead, differences in gene expression within a population of genetically identical epithelial cells can create a subpopulation with greater resistance, which, following damage, survive, alter their fate, and help regenerate the tissue.
Highlights
The ability to regenerate is critical for tissue homeostasis in adult organisms
Drosophila larvae have epithelial structures called imaginal discs that will give rise to most of the external adult structures, such as wings, limbs, or antennae; these organ precursors are formed by a single layer of epithelial cells that folds into a sac
Previous studies have shown that dying cells produce signals that activate cell proliferation of some of their neighbors, allowing them to regenerate the disc and thereby enabling the flies to develop into normal adults
Summary
The ability to regenerate is critical for tissue homeostasis in adult organisms. Many tissues such as the gut and the skin suffer constant environmental insults that result in cell death, requiring tissue-specific stem cells to proliferate and compensate for cell loss. Tumors and blood cancers are hypothesized to contain a small population of cells with greater ability to initiate new tumors than the rest Such cancer-initiating cells would help replenish the tumor, after therapy for example, or to produce new tumors at distant sites as metastases. Understanding molecular mechanisms that underlie the increased resistance of cancer-initiating cells and their ability to contribute to regrowth is essential for optimizing anticancer treatments. In this regard, genetically tractable model systems in which cells show resistance to death induced by cytotoxic agents and contribute to regeneration would be valuable tools
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