SUMMARY Adult stem cells provide a renewable source of differentiated cells for a wide variety of tissues and generally give rise to multiple cell types. Basic principles of stem cell organization and regulation underlying this behavior are emerging. Local niche signals maintain stem cells, while different sets of signals act outside the niche to diversify initially equivalent stem cell progeny. Here we show that Drosophila ovarian Follicle Stem Cells (FSCs) produced two distinct cell types directly. This cell fate choice was determined by the A/P position of an FSC and by the magnitude of spatially graded Wnt pathway activity. These findings reveal a paradigm of immediate diversification of stem cell derivatives according to stem cell position within a larger population, guided by a graded niche signal. We also found that FSCs strongly resemble mammalian intestinal stem cells in many aspects of their organization, including population asymmetry and dynamic heterogeneity.
Many adult stem cell communities are maintained by population asymmetry, where stochastic behaviors of multiple individual cells collectively result in a balance between stem cell division and differentiation. We investigated how this is achieved for Drosophila Follicle Stem Cells (FSCs) by spatially-restricted niche signals. FSCs produce transit-amplifying Follicle Cells (FCs) from their posterior face and quiescent Escort Cells (ECs) to their anterior. We show that JAK-STAT pathway activity, which declines from posterior to anterior, dictates the pattern of divisions over the FSC domain, promotes more posterior FSC locations and conversion to FCs, while opposing EC production. Wnt pathway activity declines from the anterior, promotes anterior FSC locations and EC production, and opposes FC production. The pathways combine to define a stem cell domain through concerted effects on FSC differentiation to ECs and FCs at either end of opposing signaling gradients, and impose a pattern of proliferation that matches derivative production.
Cancer-initiating gatekeeper mutations that arise in stem cells would be especially potent if they stabilize and expand an affected stem cell lineage. It is therefore important to understand how different stem cell organization strategies promote or prevent variant stem cell amplification in response to different types of mutation, including those that activate proliferation. Stem cell numbers can be maintained constant while producing differentiated products through individually asymmetrical division outcomes or by population asymmetry strategies in which individual stem cell lineages necessarily compete for niche space. We considered alternative mechanisms underlying population asymmetry and used quantitative modeling to predict starkly different consequences of altering proliferation rate: A variant, faster proliferating mutant stem cell should compete better only when stem cell division and differentiation are independent processes. For most types of stem cells, it has not been possible to ascertain experimentally whether division and differentiation are coupled. However, follicle stem cells (FSCs) provided a favorable system with which to investigate population asymmetry mechanisms and also for measuring the impact of altered proliferation on competition. We found from detailed cell lineage studies that division and differentiation of an individual FSC are not coupled. We also found that FSC representation, reflecting maintenance and amplification, was highly responsive to genetic changes that altered only the rate of FSC proliferation. The FSC paradigm therefore provides definitive experimental evidence for the general principle that relative proliferation rate will always be a major determinant of competition among stem cells specifically when stem cell division and differentiation are independent.
SUMMARYCancer-initiating gatekeeper mutations that arise in stem cells would be especially potent if they stabilize and expand an affected stem lineage (1, 2). It is therefore important to understand how different stem cell organization strategies promote or prevent variant stem cell amplification in response to different types of mutation, including those that activate stem cell proliferation. Stem cell numbers can be maintained constant while producing differentiated products through individually asymmetric division outcomes or by population asymmetry strategies, in which individual stem cell lineages necessarily compete for niche space. We considered alternative mechanisms underlying population asymmetry and used quantitative modeling to predict starkly different consequences of altering proliferation rate: a variant, faster-proliferating mutant stem cell should compete better only when stem cell division and differentiation are independent processes. For most types of stem cell it has not been possible to ascertain experimentally whether division and differentiation are coupled. However, Drosophila Follicle Stem Cells (FSCs) provided a favorable model system to investigate population asymmetry mechanisms and also for measuring the impact of altered proliferation on competition. We found from detailed cell lineage studies that FSC division and FSC differentiation are not coupled. We also found that FSC representation, reflecting maintenance and amplification, was highly responsive to genetic changes that altered only the rate of FSC proliferation. The FSC paradigm therefore provides definitive experimental evidence for the general principle that relative proliferation rate will always be a major determinant of competition among stem cells specifically when stem cell division and differentiation are independent.All rights reserved. No reuse allowed without permission.
SummaryA paper by Reilein et al., (2017) presented several key new insights into the behavior of adult Follicle Stem Cells (FSCs) in the Drosophila ovary, including overwhelming evidence that each ovariole hosts a large number of FSCs (about 14-16) maintained by population asymmetry (Reilein et al., 2017), rather than just two FSCs, dividing with largely individually asymmetric outcomes, as originally proposed (Margolis and Spradling, 1995; Nystul and Spradling, 2007). Here we provide further discussion asserting the merits of the conclusions of Reilein et al., (2017) and the deficiencies in the contrary assertions recently presented by Fadiga and Nystul (Fadiga and Nystul, 2019). The principles that we discuss here, particularly with regard to lineage tracing and population asymmetry, are common to the investigation of most types of adult stem cell and should therefore be instructive and of interest to investigators studying any type of adult stem cell. The improved understanding of FSC numbers, location and behavior afforded by Reilein et al., (2017) and Reilein et al., (2018) can only provide a firm foundation for future progress once they are widely appreciated and seen to be resistant to challenge, as described in detail here.
Drosophila ovarian Follicle Stem Cells (FSCs) present a favorable paradigm for understanding how stem cell division and differentiation are balanced in communities where they can be regulated independently. Many key extracellular signals for FSCs have been identified, including inversely graded Wnt and JAK-STAT pathway activators. FSCs also exhibit interesting functional spatial heterogeneity; posterior FSCs become proliferative Follicle Cells, while anterior FSCs become quiescent Escort Cells at a much lower rate. Here, by using live imaging and FUCCI cell-cycle reporters, we measured absolute division rates and found that posterior FSCs cycle 3-4 times faster than their anterior neighbors, matching their increased differentiation rate. We also found evidence for FSC G2/M cycling restrictions and G1/S restriction that increases more anteriorly, especially beyond the FSC domain. JAK-STAT signaling promotes both transitions but graded JAK-STAT signaling alone does not explain the graded cycling of FSCs. Genetic interaction tests and FUCCI reporter assays suggest that JAK-STAT signaling acts partly through Yorkie and can largely substitute for stimulation of division by Hh signaling. PI3 kinase signaling, in contrast to Hh signaling, acts largely independently of Yorkie induction and stimulates the G2/M transition.
SummaryA paper by Reilein et al (2017) presented several fundamental new insights into the behavior of adult Follicle Stem Cells (FSCs) in the Drosophila ovary, including evidence that each ovariole hosts a large number of FSCs (14-16) maintained by population asymmetry (Reilein et al., 2017), rather than just two FSCs, dividing with largely individually asymmetric outcomes, as originally proposed (Margolis and Spradling, 1995; Nystul and Spradling, 2007). Fadiga and Nystul (2019) contest some of these conclusions on the basis of their repetition of a multicolor lineage strategy used by Reilein et al (2017) and repetition of earlier single-color lineage analysis. Here we outline a number of shortcomings in the execution and interpretation of those experiments that, in our opinion, undermine their conclusions. The central issue of general relevance concerns the importance of comprehensively analyzing all stem cell lineages, independent of any pre-conceptions, in order to identify all constituents and capture heterogeneous behaviors.
Many adult stem cells are maintained as a community by population asymmetry, wherein stochastic actions of individual cells collectively result in a balance between stem cell division and differentiation. We have used Drosophila Follicle Stem Cells (FSCs) as a paradigm to explore the extracellular niche signals that define a stem cell domain and organize stem cell behavior. FSCs produce transit-amplifying Follicle Cells (FCs) from their posterior face and quiescent Escort Cells (ECs) to their anterior. Here we show that JAK-STAT pathway activity, which declines from posterior to anterior, dictates the pattern of divisions over the FSC and EC domains, promotes more posterior FSC locations and conversion to FCs, while opposing EC production. A Wnt pathway gradient of opposite polarity promotes more anterior FSC locations and EC production and opposes FC production. Promotion of both FSC division and conversion to FCs by JAK-STAT signaling buffers the effects of genetically altered pathway activity on FSC numbers and balances the four-fold higher rate of differentiation at the posterior face of the FSC domain with a higher rate of FSC division in the most posterior layer. However, genetic elimination of Wnt pathway activity exacerbated elevated FC production resulting from increased JAK-STAT pathway activity, leading to rapid FSC depletion despite high rates of division. The two pathways combine to define a stem cell domain through concerted effects on FSC differentiation to ECs (high Wnt, low JAK-STAT) and FCs (low Wnt, high JAK-STAT) at each end of opposing signaling gradients, further enforced by quiescence at the anterior border due to declining JAK-STAT pathway activity.
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