Division-independent differentiation mandates proliferative competition among stem cells

Abstract

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.

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

“…If each stem cell repeatedly divides to produce a stem cell and a differentiated product (‘invariant single-cell asymmetry’), the rate of division must simply be matched to the required supply of product cells. 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 is commonly not temporally or 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 likely guided substantially by extracellular signals and it is commonly presumed that regulation is achieved substantially by defining a compartment with fixed dimensions that can maintain stem cells.…”

“…The consequent deductions of FSC number, location and behavior were largely re-stated as dogma over the following two decades despite some contrary observations ( Hartman et al, 2015 ; Nystul and Spradling, 2007 ; Nystul and Spradling, 2010 ; Zhang and Kalderon, 2001 ). A comprehensive re-evaluation, which included the analysis of all FSC lineages, without any prior assumptions about their behavior, showed that individual FSCs were frequently lost or duplicated ( Reilein et al, 2017 ) and that FSC differentiation to an FC was not temporally coupled to, or dependent upon division of the same FSC ( Reilein et al, 2018 ). These characteristics of maintenance by population asymmetry, together with independent cell division and cell differentiation events and decisions, are shared by two very important and intensively studied types of mammalian epithelial stem cell, in the gut and in the epidermis ( Jones, 2010 ; Mesa et al, 2018 ; Ritsma et al, 2014 ; Rompolas et al, 2016 ).…”

“…Production of 5–6 ‘founder’ FCs (the first FCs to associate with a germline cyst to seed the FC epithelium) per budding cycle is accomplished by 14–16 FSCs, arranged in three anterior-posterior (AP) rings anterior to the border of strong Fas3 protein expression, near the mid-point of the germarium ( Figure 1A–D ; 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 ).…”

“…FSCs also exhibit extensive radial movements tracked by live imaging, and no radial germarium asymmetries are known, suggesting that all FSCs within a layer are equivalent ( Reilein et al, 2017 ). Posterior FSCs divide faster than anterior FSCs, so that the roughly four-fold greater efflux of derivatives 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 ; Reilein et al, 2018 ). Thus, FSCs present a paradigm of dynamic heterogeneity ( Greulich and Simons, 2016 ), where each stem cell within a fluid spatially-defined community exhibits distinctive instantaneous properties characteristic of its precise AP location but future behavior can change as a result of apparently stochastic changes in position or cell division.…”

“…The key role of FSC division rate for FSC competition was highlighted by studies of Hh signaling and 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 ). A functional connection between stem cell division rate and competition is not expected for stem cells maintained by invariant single-cell asymmetry and was finally explained by the finding that FSC differentiation is independent of FSC division ( Reilein et al, 2018 ).…”