Dynamic heterogeneity as a strategy of stem cell self-renewal

Significance In many tissues, such as intestine and skin, cells are constantly turned over throughout life. To replenish cells that are lost, new cells are generated by stem cells, which divide and differentiate to maintain tissue in a steady state. The mechanisms that allow stem cells to achieve perfect self-renewal promise fundamental insights into processes leading to diseased states. Efforts to define strategies of stem cell self-renewal have placed emphasis on models in which stem cells progress one way through a differentiation hierarchy. Here, we show that a different paradigm, in which stem cells transfer reversibly between states primed for renewal or poised for differentiation, offers a viable and robust mechanism of tissue self-renewal. To maintain cycling adult tissue in homeostasis the balance between proliferation and differentiation of stem cells needs to be precisely regulated. To investigate how stem cells achieve perfect self-renewal, emphasis has been placed on models in which stem cells progress sequentially through a one-way proliferative hierarchy. However, investigations of tissue regeneration have revealed a surprising degree of flexibility, with cells normally committed to differentiation able to recover stem cell competence following injury. Here, we investigate whether the reversible transfer of cells between states poised for proliferation or differentiation may provide a viable mechanism for a heterogeneous stem cell population to maintain homeostasis even under normal physiological conditions. By addressing the clonal dynamics, we show that such models of “dynamic heterogeneity” may be equally capable of describing the results of recent lineage tracing assays involving epithelial tissues. Moreover, together with competition for limited niche access, such models may provide a mechanism to render tissue homeostasis robust. In particular, in 2D epithelial layers, we show that the mechanism of dynamic heterogeneity avoids some pathological dependencies that undermine models based on a hierarchical stem/progenitor organization.