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: We next considered whether, in turn, normal cells could be affected by the presence of suboptimal cells and what impact this might have on their tissue-colonization potential. Although the clonal competition assay (Figure 2C) shows that wild-type cells have a clonal advantage over M−/+ cells, this might result solely from their intrinsically faster proliferation rate, a phenomenon known as biased competition (Snippert et al., 2014). Indeed, wild-type ISCs divide significantly faster than M−/+ ISCs in this tissue (Figures S2A–S2C), and cell-autonomous differences in proliferation rate have been proposed to account entirely for the clonal expansion of wild-type clones during Minute competition in wing imaginal discs (Martín et al., 2009). To address this, we compared the behavior of control wild-type clones surrounded by wild-type cells to that of wild-type clones surrounded by M−/+ cells by lineage tracing (Figures 3A–3C) at different time points. Because in both setups the genotype of wild-type cells was identical, any change we observed between the two conditions would have to be a consequence of the interaction with M−/+ cells. Interestingly, wild-type stem cells grew into bigger clones when surrounded by M−/+ cells (Figure 3C). This was observed at early (3-day) and especially at late (20-day) time points ACI. Importantly, increased clone expansion was not a general feature of cells in M−/+ guts, because control M−/+ ISCs formed smaller clones in M−/+ guts (Figures S2D–S2F), consistent with their reduced proliferation rate (Figures S2A–S2C). Furthermore, whereas control clones grew in a manner consistent with homeostatic behavior (i.e., the average number of labeled progeny tended to plateau after initial growth, consistent with proliferation balanced by loss; de Navascués et al., 2012), competing wild-type clones expanded nonhomeostatically (Figure 3D).
Affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.