Division-independent differentiation mandates proliferative competition among stem cells

Abstract

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.

Opposing Wnt and JAK-STAT signaling gradients define a stem cell domain by regulating spatially patterned cell division and differentiation at two borders

“…The observed distribution at 6d was quite different from the assumed starting distribution, most obviously because more than a third of ovarioles no longer include any FSCs while the proportion of ovarioles with six or more FSCs has increased ( Fig. 1G), consistent with expectations for neutral competition (Jones, 2010;Reilein et al, 2017;Reilein et al, 2018). These changes were further exaggerated at 12d but full colonization of a germarium by marked cells generally takes longer (Reilein et al, 2017), so even at 12d marked FSCs remain in a minority and are competing against unmarked wild-type cells in almost all ovarioles ( Fig.…”

“…More commonly, however, a group of stem cells in a given location is maintained by "population asymmetry", where individual stem cells exhibit non-uniform, stochastic behaviors and differentiation need not be mechanistically linked to division of the same stem cell (Reilein et al, 2018;Ritsma et al, 2014;Rompolas et al, 2016;Simons and Clevers, 2011). The behavior of such stem cells is substantially guided by extracellular signals, raising the important questions of how such signals might define niche space and the number of stem cells accommodated, how they affect stem cell division and differentiation, and whether they co-ordinate those two fundamental behaviors.…”

“…Production of 5-6 "founder" FCs (proliferative precursors of mature FCs) per budding cycle is accomplished by 14-16 FSCs, arranged in three anterior-posterior (AP) rings near the mid-point of the germarium (Fig. 1A) (Hayashi et al, 2020;Reilein et al, 2017;Reilein et al, 2018). These FSCs also produce a second cell type known as an Escort Cell (EC) (Hayashi et al, 2020;Reilein et al, 2017).…”

“…Posterior FSCs divide faster than anterior FSCs, so that the greater efflux from the posterior face of the FSC domain is supported without significant net flow of FSCs from anterior to posterior locations (Reilein et al, 2017). FSC division and differentiation to a FC are separate events; they are not temporally or functionally coupled in an individual FSC (Reilein et al, 2018). Thus, FSCs present a paradigm of dynamic heterogeneity (Greulich and Simons, 2016), wherein a community of stem cells exists within a defined spatial domain and constituent stem cells exhibit both distinctive instantaneous properties according to precise AP location and fluid, apparently stochastic changes in position and behavior over time.…”

“…Hh was shown to influence FSC behavior principally by regulating the rate of FSC division through transcriptional induction of the Hippo-pathway transcriptional co-activator Yorkie (Yki) (Huang and Kalderon, 2014). The key role of FSC division rate for FSC competition was highlighted also by the discovery of several regulators of proliferation in a genetic screen for FSC maintenance factors (Wang et al, 2012;Wang and Kalderon, 2009), and was explained by the finding that FSC differentiation is independent of FSC division (i.e., these are two separate processes) (Reilein et al, 2018).…”