Cell Competition Modifies Adult Stem Cell and Tissue Population Dynamics in a JAK-STAT-Dependent Manner.
Bottom Line: We address this question using the adult Drosophila posterior midgut as a model of homeostatic tissue and ribosomal Minute mutations to reduce fitness in groups of cells.We also find that competition induces stem cell proliferation and self-renewal in healthy tissue, promoting selective advantage and tissue colonization.Finally, we show that winner cell proliferation is fueled by the JAK-STAT ligand Unpaired-3, produced by Minute(-/+) cells in response to chronic JNK stress signaling.
Affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.Show MeSH
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Mentions: Induction of death in weaker cells is a major hallmark of cell competition. To look for evidence of cell competition in the posterior midgut, we therefore asked whether wild-type intestinal cells induce accelerated turnover of neighboring M−/+ cells. Depending on the experiment, here and throughout this study, we induced either the formation of wild-type (M+/+) clones in a M−/+ gut or, vice versa, we generated M−/+ clones in a (pseudo) wild-type gut. Clones were induced in recently eclosed adults by heat shock-induced, Flp-mediated mitotic recombination. In the posterior midgut, cells that are turned over are shed into the intestinal lumen following epithelial delamination. Consistent with our hypothesis, we found that in mosaic guts containing wild-type and M−/+ cells, delaminated cells (normalized to the abundance of each cell population) were more likely to be M−/+ than wild-type (Figures 1A–1C). This indicated that in competing guts, M−/+ cells have an accelerated turnover compared to wild-type cells. However, although their relatively shorter lifetime could be a consequence of their interaction with wild-type cells, it could also result from the M−/+ mutation per se. To test the latter possibility, we compared relative turnover rates of wholly wild-type and wholly M−/+ posterior midguts using a previously published genetic tool that allows pulse labeling all cells in a gut and then chasing to monitor how long they persist (Jiang et al., 2009). This revealed that, in fact, cell turnover in M−/+ guts is slower than in wild-type guts (Figures S1A–S1D). This rules out the possibility that the accelerated turnover observed in competing guts is an intrinsic property of M−/+ cells and suggests that it is induced by cell competition. Next, we compared directly the relative cell-death frequency of M−/+ cells close to wild-type cells and of M−/+ cells far away (i.e., greater than two cell diameters away; see Experimental Procedures) from wild-type cells within the same guts using the cell-death marker Sytox (Figures 1D and 1E; Figures S1E–S1F″). Importantly, the cell-death frequency of M−/+ cells was specifically increased in the proximity of wild-type cells (Figures 1D and 1E), indicating that this was a result of cell-cell interaction. This finding was further confirmed by analysis of PARP cleavage (Figures 1F–1F″), a readout of caspase activation (Williams et al., 2006) (Figures S1E–S1F″), which also indicates that (at least some) cells die of apoptosis.
Affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.