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Cell Competition Modifies Adult Stem Cell and Tissue Population Dynamics in a JAK-STAT-Dependent Manner.

Kolahgar G, Suijkerbuijk SJ, Kucinski I, Poirier EZ, Mansour S, Simons BD, Piddini E - Dev. Cell (2015)

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.

View Article: PubMed Central - PubMed

Affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.

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Adult Tissue Dynamics and Signaling Pathways during Minute Competition(A) Active cell competition between healthy and subfit cells in the Drosophila homeostatic midgut causes loss of subfit tissue. M−/+ differentiated cells are eliminated via apoptosis and M−/+ ISCs are lost, possibly by cell death or induction of differentiation (left). Conversely, the presence of unhealthy tissue promotes expansion of healthy stem cells and their progeny. ISCs increase their proliferation rate and their symmetric self-renewal, which fuels clonal expansion (right).(B) M−/+ cells drive the clonal expansion of fit cells through an inflammatory-like response. Chronic JNK signaling activation in M−/+ cells activates constitutive expression of the JAK-STAT ligand Unpaired-3. Secreted Unpaired-3, via binding to its receptor Dome, activates JAK-STAT signaling, stimulating the proliferative expansion of wild-type clones during cell competition.
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fig7: Adult Tissue Dynamics and Signaling Pathways during Minute Competition(A) Active cell competition between healthy and subfit cells in the Drosophila homeostatic midgut causes loss of subfit tissue. M−/+ differentiated cells are eliminated via apoptosis and M−/+ ISCs are lost, possibly by cell death or induction of differentiation (left). Conversely, the presence of unhealthy tissue promotes expansion of healthy stem cells and their progeny. ISCs increase their proliferation rate and their symmetric self-renewal, which fuels clonal expansion (right).(B) M−/+ cells drive the clonal expansion of fit cells through an inflammatory-like response. Chronic JNK signaling activation in M−/+ cells activates constitutive expression of the JAK-STAT ligand Unpaired-3. Secreted Unpaired-3, via binding to its receptor Dome, activates JAK-STAT signaling, stimulating the proliferative expansion of wild-type clones during cell competition.

Mentions: Recent studies have shown that cell competition can also take place in adult tissues (Oertel et al., 2006; Villa del Campo et al., 2014). Our work has taken this notion forward and delineated quantitatively how adult stem cells and tissue population dynamics are affected by cell competition (Figure 7A). In the subfit population, differentiated cells are killed by apoptosis followed by cell delamination; stem cells are also eliminated, possibly via induction of differentiation, as we have not detected dying stem cells. In parallel, as we show, the healthy tissue expands due to an increase in stem cell proliferation and self-renewal. Indeed, biophysical modeling shows that changes in these parameters of a magnitude comparable to what we observe experimentally is sufficient to recapitulate the stem cell dynamics of wild-type tissue undergoing Minute cell competition. Interestingly, accelerated proliferation of fitter stem cells has been seen in mouse embryonic stem cells using in vitro models of cell competition (Clavería et al., 2013; Sancho et al., 2013). However, in those studies, increased stem cell self-renewal has not been observed, probably because stemness in vitro is artificially maintained by exogenous factors in the culture medium.


Cell Competition Modifies Adult Stem Cell and Tissue Population Dynamics in a JAK-STAT-Dependent Manner.

Kolahgar G, Suijkerbuijk SJ, Kucinski I, Poirier EZ, Mansour S, Simons BD, Piddini E - Dev. Cell (2015)

Adult Tissue Dynamics and Signaling Pathways during Minute Competition(A) Active cell competition between healthy and subfit cells in the Drosophila homeostatic midgut causes loss of subfit tissue. M−/+ differentiated cells are eliminated via apoptosis and M−/+ ISCs are lost, possibly by cell death or induction of differentiation (left). Conversely, the presence of unhealthy tissue promotes expansion of healthy stem cells and their progeny. ISCs increase their proliferation rate and their symmetric self-renewal, which fuels clonal expansion (right).(B) M−/+ cells drive the clonal expansion of fit cells through an inflammatory-like response. Chronic JNK signaling activation in M−/+ cells activates constitutive expression of the JAK-STAT ligand Unpaired-3. Secreted Unpaired-3, via binding to its receptor Dome, activates JAK-STAT signaling, stimulating the proliferative expansion of wild-type clones during cell competition.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4537514&req=5

fig7: Adult Tissue Dynamics and Signaling Pathways during Minute Competition(A) Active cell competition between healthy and subfit cells in the Drosophila homeostatic midgut causes loss of subfit tissue. M−/+ differentiated cells are eliminated via apoptosis and M−/+ ISCs are lost, possibly by cell death or induction of differentiation (left). Conversely, the presence of unhealthy tissue promotes expansion of healthy stem cells and their progeny. ISCs increase their proliferation rate and their symmetric self-renewal, which fuels clonal expansion (right).(B) M−/+ cells drive the clonal expansion of fit cells through an inflammatory-like response. Chronic JNK signaling activation in M−/+ cells activates constitutive expression of the JAK-STAT ligand Unpaired-3. Secreted Unpaired-3, via binding to its receptor Dome, activates JAK-STAT signaling, stimulating the proliferative expansion of wild-type clones during cell competition.
Mentions: Recent studies have shown that cell competition can also take place in adult tissues (Oertel et al., 2006; Villa del Campo et al., 2014). Our work has taken this notion forward and delineated quantitatively how adult stem cells and tissue population dynamics are affected by cell competition (Figure 7A). In the subfit population, differentiated cells are killed by apoptosis followed by cell delamination; stem cells are also eliminated, possibly via induction of differentiation, as we have not detected dying stem cells. In parallel, as we show, the healthy tissue expands due to an increase in stem cell proliferation and self-renewal. Indeed, biophysical modeling shows that changes in these parameters of a magnitude comparable to what we observe experimentally is sufficient to recapitulate the stem cell dynamics of wild-type tissue undergoing Minute cell competition. Interestingly, accelerated proliferation of fitter stem cells has been seen in mouse embryonic stem cells using in vitro models of cell competition (Clavería et al., 2013; Sancho et al., 2013). However, in those studies, increased stem cell self-renewal has not been observed, probably because stemness in vitro is artificially maintained by exogenous factors in the culture medium.

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.

View Article: PubMed Central - PubMed

Affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.

Show MeSH
Related in: MedlinePlus