Feedback regulation in multistage cell lineages

Abstract

Studies of developing and self-renewing tissues have shown that differentiated cell types are typically specified through the actions of multistage cell lineages. Such lineages commonly include a stem cell and multiple progenitor (transit amplifying; TA) cell stages, which ultimately give rise to terminally differentiated (TD) cells. In several cases, self-renewal and differentiation of stem and progenitor cells within such lineages have been shown to be under feedback regulation. Together, the existence of multiple cell stages within a lineage and complex feedback regulation are thought to confer upon a tissue the ability to autoregulate development and regeneration, in terms of both cell number (total tissue volume) and cell identity (the proportions of different cell types, especially TD cells, within the tissue). In this paper, we model neurogenesis in the olfactory epithelium (OE) of the mouse, a system in which the lineage stages and mediators of feedback regulation that govern the generation of terminally differentiated olfactory receptor neurons (ORNs) have been the subject of much experimental work. Here we report on the existence and uniqueness of steady states in this system, as well as local and global stability of these steady states. In particular, we identify parameter conditions for the stability of the system when negative feedback loops are represented either as Hill functions, or in more general terms. Our results suggest that two factors – autoregulation of the proliferation of transit amplifying (TA) progenitor cells, and a low death rate of TD cells – enhance the stability of this system.

The zebrafish flotte lotte mutant reveals that the local retinal environment promotes the differentiation of proliferating precursors emerging from their stem cell niche

“…Thus, our data are consistent with models employing environmental feedback to control progenitor cell behaviour in cell lineages and stem cell niches (e.g. Lander et al, 2009;Lo et al, 2009).…”

“…Multiple extrinsic feedback loops provide stability in the regulation of proliferating progenitors Lo et al, 2009). We suspect that the intrinsic properties of flo cells -DNA replication errors (Davuluri et al, 2008), slowed cell cycle progression and inefficient neurogenesis (this study) -perturb the flo retina such that the normal feedback signals governing proliferation and differentiation are imbalanced.…”

Ovol2 Suppresses Cell Cycling and Terminal Differentiation of Keratinocytes by Directly Repressing c-Myc and Notch1

“…Mathematic Modeling Suggests That Ovol2 Suppresses the Rate of Keratinocyte Cycling but Prolongs the Number of Divisions They Undergo-To explore the cellular basis of these seemingly contradictory observations, we applied a simple cell lineage mathematic model (33,34) to examine keratinocyte stem/progenitor cell evolution. We considered three distinct cell types (42): slow cycling stem cells that can proliferate indefinitely, faster cycling progenitor cells with a set proliferation potential (indicated by M number of cell divisions they are able to undergo), and growth-arrested cells (Fig.…”

Dynamical modelling of haematopoiesis: an integrated view over the system in homeostasis and under perturbation

“…the oscillatory behaviour of HSC [15,16], regulation of erythropoiesis [17,18], T-cell production [19] or the effects of ageing on B-cell development [20]. Other models have focused on fundamental structural and functional properties of haematopoiesis, such as the regulation of self-renewal [21,22], the characterization of the stem cell population as the most sensitive to environmental signals out of all haematopoietic cell populations [11], the importance of signalling factors on the decision to self-renew or differentiate, depending, for example, on the number of fully differentiated cells [23,24], the role of feedback control mechanisms [25][26][27] and lineage specification principles [28]. More global attempts describe haematopoiesis from HSC to mature cells, but mostly implementing simplified architectures, either by not explicitly considering the different lineages and branching points [29], or by doing so at a course grained level.…”