The Degeneracy of Control Architectures in Cell Lineages: Implications for Tissue Homeostasis (original) (raw)
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Feedback regulation in multistage cell lineages
Mathematical Biosciences and Engineering, 2008
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.
Cell Lineages and the Logic of Proliferative Control
PLoS Biology, 2009
It is widely accepted that the growth and regeneration of tissues and organs is tightly controlled. Although experimental studies are beginning to reveal molecular mechanisms underlying such control, there is still very little known about the control strategies themselves. Here, we consider how secreted negative feedback factors (''chalones'') may be used to control the output of multistage cell lineages, as exemplified by the actions of GDF11 and activin in a self-renewing neural tissue, the mammalian olfactory epithelium (OE). We begin by specifying performance objectives-what, precisely, is being controlled, and to what degree-and go on to calculate how well different types of feedback configurations, feedback sensitivities, and tissue architectures achieve control. Ultimately, we show that many features of the OE-the number of feedback loops, the cellular processes targeted by feedback, even the location of progenitor cells within the tissue-fit with expectations for the best possible control. In so doing, we also show that certain distinctions that are commonly drawn among cells and molecules-such as whether a cell is a stem cell or transit-amplifying cell, or whether a molecule is a growth inhibitor or stimulator-may be the consequences of control, and not a reflection of intrinsic differences in cellular or molecular character.
A Computational Model of Stem Cell Molecular Mechanism to Maintain Tissue Homeostasis
Stem cells, with their capacity to self-renew and to differentiate to more specialized cell types, play a key role to maintain homeostasis in adult tissues. To investigate how, in the dynamic stochastic environment of a tissue, non-genetic diversity and the precise balance between proliferation and differentiation are achieved, it is necessary to understand the molecular mechanisms of the stem cells in decision making process. By focusing on the impact of stochasticity, we proposed a computational model describing the regulatory circuitry as a tri-stable dynamical system to reveal the mechanism which orchestrate this balance. Our model explains how the distribution of noise in genes, linked to the cell regulatory networks, controls cell decision-making to maintain homeostatic state. The noise control over tissue homeostasis is achieved by regulating the probability of differentiation and self-renewal through symmetric and/or asymmetric cell divisions. Our model reveals, when mutatio...
Understanding cell lineages as complex adaptive systems
Blood Cells Molecules and Diseases, 2004
Stem cells may be considered complex reactive systems because of their vast number in a living system, their reactive nature, and the influence of local environmental factors (such as the state of neighboring cells, tissue matrix, stem cell physiological processes) on their behavior. In such systems, emergent global behavior arises through the multitude of local interactions among the cell agents. Approaching hematopoietic and other stem cell lineages from this perspective have critical ramifications on current thinking relating to the plasticity of these lineage systems, the modeling of stem cell systems, and the interpretation of clinical data regarding many diseases within such models.
Feedback, Lineages and Self-Organizing Morphogenesis
PLOS Computational Biology, 2016
Feedback regulation of cell lineage progression plays an important role in tissue size homeostasis, but whether such feedback also plays an important role in tissue morphogenesis has yet to be explored. Here we use mathematical modeling to show that a particular feedback architecture in which both positive and negative diffusible signals act on stem and/or progenitor cells leads to the appearance of bistable or bi-modal growth behaviors, ultrasensitivity to external growth cues, local growth-driven budding, self-sustaining elongation, and the triggering of self-organization in the form of lamellar fingers. Such behaviors arise not through regulation of cell cycle speeds, but through the control of stem or progenitor self-renewal. Even though the spatial patterns that arise in this setting are the result of interactions between diffusible factors with antagonistic effects, morphogenesis is not the consequence of Turing-type instabilities.
Emergence of Rules in Cell Society: Differentiation, Hierarchy, and Stability
Bulletin of Mathematical Biology, 1998
A dynamic model for cell differentiation is studied, where cells with internal chemical reaction dynamics interact with each other and replicate. It leads to spontaneous differentiation of cells and determination, as is discussed in the isologous diversification. Following features of the differentiation are obtained: (1)Hierarchical differentiation from a "stem" cell to other cell types, with the emergence of the interactiondependent rules for differentiation; (2)Global stability of an ensemble of cells consisting of several cell types, that is sustained by the emergent, autonomous control on the rate of differentiation; (3)Existence of several cell colonies with different cell-type distributions. The results provide a novel viewpoint on the origin of complex cell society, while relevance to some biological problems, especially to the hemopoietic system, is also discussed.
Cell lineage branching as a strategy for proliferative control
BMC Biology, 2015
Background: How tissue and organ sizes are specified is one of the great unsolved mysteries in biology. Experiments and mathematical modeling implicate feedback control of cell lineage progression, but a broad understanding of what lineage feedback accomplishes is lacking. Results: By exploring the possible effects of various biologically relevant disturbances on the dynamic and steady state behaviors of stem cell lineages, we find that the simplest and most frequently studied form of lineage feedback-which we term renewal control-suffers from several serious drawbacks. These reflect fundamental performance limits dictated by universal conservation-type laws, and are independent of parameter choice. Here we show that introducing lineage branches can circumvent all such limitations, permitting effective attenuation of a wide range of perturbations. The type of feedback that achieves such performance-which we term fate control-involves promotion of lineage branching at the expense of both renewal and (primary) differentiation. We discuss the evidence that feedback of just this type occurs in vivo, and plays a role in tissue growth control. Conclusions: Regulated lineage branching is an effective strategy for dealing with disturbances in stem cell systems. The existence of this strategy provides a dynamics-based justification for feedback control of cell fate in vivo.
Perspective: Stem cells react! Cell lineages as complex adaptive systems
Experimental Hematology, 2004
It may be argued that adult stem cell processes or, more precisely, the cell lineages that arise from them, represent complex reactive or adaptive systems. Approaching hematopoietic and other stem cell lineages from this perspective has direct bearing on current debates regarding the plasticity of these lineage systems as well as on interpretation and modeling of clinical data regarding many diseases. Ć 2004 International Society for Experimental Hematology.
Growth, homeostatic regulation and stem cell dynamics in tissues
Journal of The Royal Society Interface, 2014
The regulation of cell growth in animal tissues is a question of critical importance: most tissues contain different types of cells in interconversion and the fraction of each type has to be controlled in a precise way, by mechanisms that remain unclear. Here, we provide a theoretical framework for the homeostasis of stem-cell-containing epithelial tissues using mechanical equations, which describe the size of the tissue and kinetic equations, which describe the interconversions of the cell populations. We show that several features, such as the evolution of stem cell fractions during intestinal development, the shape of a developing intestinal wall, as well as the increase in the proliferative compartment in cancer initiation, can be studied and understood from generic modelling which does not rely on a particular regulatory mechanism. Finally, inspired by recent experiments, we propose a model where cell division rates are regulated by the mechanical stresses in the epithelial she...
Philosophical Transactions of the Royal Society B: Biological Sciences, 2011
Stem cell behaviours, such as stabilization of the undecided state of pluripotency or multipotency, the priming towards a prospective fate, binary fate decisions and irreversible commitment, must all somehow emerge from a genome-wide gene-regulatory network. Its unfathomable complexity defies the standard mode of explanation that is deeply rooted in molecular biology thinking: the reduction of observables to linear deterministic molecular pathways that are tacitly taken as chains of causation. Such culture of proximate explanation that uses qualitative arguments, simple arrow–arrow schemes or metaphors persists despite the ceaseless accumulation of ‘omics’ data and the rise of systems biology that now offers precise conceptual tools to explain emergent cell behaviours from gene networks. To facilitate the embrace of the principles of physics and mathematics that underlie such systems and help to bridge the gap between the formal description of theorists and the intuition of experime...