Cell Competition Modifies Adult Stem Cell and Tissue Population Dynamics in a JAK-STAT-Dependent Manner.
Bottom Line: Throughout their lifetime, cells may suffer insults that reduce their fitness and disrupt their function, and it is unclear how these potentially harmful cells are managed in adult tissues.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.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 first addressed the clonal dynamics of the control wild-type and control M−/+ epithelium (i.e., wild-type clones in a wild-type background and M−/+ clones in a M−/+ background) as a basis before turning to consider the dynamics of competing cells. Details of the modeling procedure, which mirror the methods introduced in de Navascués et al. (2012), are detailed in Experimental Procedures. Briefly, to model the dynamics of stem cells and their differentiated progeny, we considered a simple lattice model in which ISCs form a single equipotent population distributed uniformly within the epithelium. Alongside ISCs, each lattice site is associated with a fixed number of differentiating cells. To model turnover, we adopted an approach based on stochastic simulation in which a mature differentiated cell is chosen at random and removed. Following its loss, with a given probability either the ISC on the same site undergoes asymmetric cell division, giving rise to a replacement EC, or the ISC commits to EB/EC cell fate and is itself replaced by the symmetrical duplication of an ISC at a neighboring site. Alongside the overall cell-division rate (equivalently, under homeostasis, the loss rate of differentiated cells), the relative probability of symmetric versus asymmetric cell division defines in full the dynamics of the system. Using the datasets of control wild-type clones in Figure 3 and of M−/+ control clones in Figure S2, we found that the clonal fate data showed the predicted convergence to a cumulative clone-size distribution of approximately exponential form (Figure 4A). To make a quantitative fit of the model dynamics to the data, we considered the distribution of clone sizes as measured by their Dl+ ISC content (Figure 4A, insets). We found that the model provides a good fit to the measured cumulative clone-size distributions at all three time points in both the wild-type and the M−/+ control (Figure 4A, insets) and predicts with good approximation the total cell-number distribution at all three time points (Figure 4A, main graphs). Thus, both control wild-type (as expected) and neutral M−/+ ISCs from our experiments undergo population asymmetric self-renewal. Interestingly, from a fit to the 3- and 7-day time points, we observed that the average ISC division rate for M−/+ cells is about a factor of 2 smaller than for wild-type cells, consistent with our mitotic index data (Figures S2A–S2C).
Affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.