Dynamic heterogeneity as a strategy of stem cell 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.
Cavendish Laboratory, University of Cambridge, Cambridge CB3 0HE, United Kingdom; Wellcome Trust/Cancer Research UK Gurdon Institute, Cambridge CB2 1QN, United Kingdom; bds10@cam.ac.uk pg409@cam.ac.uk.
Philip
P
Greulich
Cavendish Laboratory, University of Cambridge, Cambridge CB3 0HE, United Kingdom; Wellcome Trust/Cancer Research UK Gurdon Institute, Cambridge CB2 1QN, United Kingdom; Wellcome Trust/Medical Research Council Stem Cell Institute, Cambridge CB2 1QR, United Kingdom bds10@cam.ac.uk pg409@cam.ac.uk.
Benjamin D
BD
Simons
D000818:Animals; D000066673:Cell Self Renewal; D008954:Models, Biological
clonal dynamics; stem cell fate; stem cell heterogeneity; tissue homeostasis