Cell dynamics and gene expression control in tissue homeostasis and development

Abstract

During tissue and organ development and maintenance, the dynamic regulation of cellular proliferation and differentiation allows cells to build highly elaborate structures. The development of the vertebrate retina or the maintenance of adult intestinal crypts, for instance, involves the arrangement of newly created cells with different phenotypes, the proportions of which need to be tightly controlled. While some of the basic principles underlying these processes developing and maintaining these organs are known, much remains to be learnt from how cells encode the necessary information and use it to attain those complex but reproducible arrangements. Here, we review the current knowledge on the principles underlying cell population dynamics during tissue development and homeostasis. In particular, we discuss how stochastic fate assignment, cell division, feedback control and cellular transition states interact during organ and tissue development and maintenance in multicellular organisms. We propose a framework, involving the existence of a transition state in which cells are more susceptible to signals that can affect their gene expression state and influence their cell fate decisions. This framework, which also applies to systems much more amenable to quantitative analysis like differentiating embryonic stem cells, links gene expression programmes with cell population dynamics.

Accelerated cell divisions drive the outgrowth of the regenerating spinal cord in axolotls

“…The influx of cells that we identified could also contribute to increasing cell numbers in the regenerating spinal cord (Figure 2I–K). To assess the contribution of these cellular mechanisms to the outgrowth time-course, we used a quantitative mathematical modeling framework (Greulich and Simons, 2016; Rué and Martinez Arias, 2015; Oates et al, 2009). We formalized the influence of each cellular mechanism on the total number of proliferative and quiescent SOX2 + cells in the high-proliferation zone in a mathematical model of cell numbers (Figure 3A, see Materials and methods, Equations 3 and 4).…”

“…To simultaneously evaluate the importance of cell proliferation, cell influx and activation of quiescent cells in the outgrowth of the spinal cord we performed a data-driven modeling approach (Greulich and Simons, 2016; Rué and Martinez Arias, 2015; Oates et al, 2009). This approach allows to establish causal relationship between the individually quantified cellular processes and it has been previously employed to unravel the stem cell dynamics during spinal cord development in chick and mouse (Kicheva et al, 2014).…”

MicroRNA-22 controls interferon alpha production and erythroid maturation in response to infectious stress in mice

“…These findings validate a prior report by Song et al in which over-expression of miR-22 led to an accumulation of stage II erythroid progenitors 17 . Thus, similar to many developmental systems that contain auto-regulatory features to control the pace of differentiation 37 , miR-22 appears to serve a regulatory role to control the pace of erythropoiesis – by slowing the stage II–III erythroid transition. Our data are consistent with the potential for rapid exhaustion of early erythrocyte progenitors in stressed mice lacking such inhibitory regulation.…”

Modeling heterogeneity in the pluripotent state: A promising strategy for improving the efficiency and fidelity of stem cell differentiation

“…Furthermore, similar to cellular reprogramming 78, during differentiation there seem to exist specific primed subpopulations of cells that are able to differentiate to specific cell types via pre‐existing pathways defined by their initial transcriptional and epigenetic states, as previously suggested 68. In addition, other cells outside of this primed subpopulation can also potentially enter these pathways as a result of stochastic events triggering transitions among cell subpopulations 5, 79, and thus, over time, reach a differentiated state. Consequently, a cell population shift can occur from the pluripotent state to the differentiated state.…”

“…A differential use of these regulatory determinants can mediate differentiation to distinct cell fates. Moreover, experimental results indicate that PSCs may exit the pluripotent state via a continuum of intermediate states, which ultimately become primed for lineage specification 2, 79. In this regard, there is compelling evidence of the biological role of NSCs heterogeneity in vivo, which are activated in the brain in response to ischemia through interferon‐γ signalling activation of dormant NSCs subpopulations, to enter a primed state 56.…”