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Principles of regulation of self-renewing cell lineages.

Komarova NL - PLoS ONE (2013)

Bottom Line: The feedback can be positive or negative in nature.Some of the control mechanisms that we find have been proposed before, but most of them are new, and we describe evidence for their existence in data that have been previously published.By specifying the types of feedback interactions that can maintain homeostasis, our mathematical analysis can be used as a guide to experimentally zero in on the exact molecular mechanisms in specific tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Mathematics, University of California Irvine, Irvine, California, United States of America.

ABSTRACT
Identifying the exact regulatory circuits that can stably maintain tissue homeostasis is critical for our basic understanding of multicellular organisms, and equally critical for identifying how tumors circumvent this regulation, thus providing targets for treatment. Despite great strides in the understanding of the molecular components of stem-cell regulation, the overall mechanisms orchestrating tissue homeostasis are still far from being understood. Typically, tissue contains the stem cells, transit amplifying cells, and terminally differentiated cells. Each of these cell types can potentially secrete regulatory factors and/or respond to factors secreted by other types. The feedback can be positive or negative in nature. This gives rise to a bewildering array of possible mechanisms that drive tissue regulation. In this paper, we propose a novel method of studying stem cell lineage regulation, and identify possible numbers, types, and directions of control loops that are compatible with stability, keep the variance low, and possess a certain degree of robustness. For example, there are exactly two minimal (two-loop) control networks that can regulate two-compartment (stem and differentiated cell) tissues, and 20 such networks in three-compartment tissues. If division and differentiation decisions are coupled, then there must be a negative control loop regulating divisions of stem cells (e.g. by means of contact inhibition). While this mechanism is associated with the highest robustness, there could be systems that maintain stability by means of positive divisions control, coupled with specific types of differentiation control. Some of the control mechanisms that we find have been proposed before, but most of them are new, and we describe evidence for their existence in data that have been previously published. By specifying the types of feedback interactions that can maintain homeostasis, our mathematical analysis can be used as a guide to experimentally zero in on the exact molecular mechanisms in specific tissues.

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Minimal regulatory networks for a two-compartment system.(a) Networks with two control loops. (b) Networks with three control loops. The circles marked with “S” and “D” denote stem and differentiated cells respectively. The two cell fate decisions are marked as “div” for divisions and “diff” for differentiation. Positive and negative bow-shaped arrows denote control loops.
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pone-0072847-g002: Minimal regulatory networks for a two-compartment system.(a) Networks with two control loops. (b) Networks with three control loops. The circles marked with “S” and “D” denote stem and differentiated cells respectively. The two cell fate decisions are marked as “div” for divisions and “diff” for differentiation. Positive and negative bow-shaped arrows denote control loops.

Mentions: In accordance with the first two observations listed above, we can identify the most minimalistic control mechanisms compatible with stability. They only include two controls, and are depicted in figure 2(a). There, we present the self-renewing cell lineage as a sequence of two decisions: a division decision of a stem cell, followed by a differentiation decision (which, if positive, results in the production of two differentiated cells). The positive and negative bow-shaped arrows represent control loops. They originate in the respective populations exerting the control. The first minimal control pattern (considered in [58], [61]) contains a negative control of stem cell divisions, e.g. as a result of contact inhibition, and a negative control of differentiation decisions from downstream (the more differentiated cells there are in the system, the less likely the stem cells will be to differentiate). The second minimal control contains a negative regulation of divisions by differentiated cells (which could also be a type of “crowd-control”), and a positive regulation of differentiation by the stem cells. The latter control loop could be a result of a self-renewal-promoting factor being secreted by a stem cell niche, in which case the more stem cells there are, the less likely each of them will self-renew, resulting in a higher differentiating probability.


Principles of regulation of self-renewing cell lineages.

Komarova NL - PLoS ONE (2013)

Minimal regulatory networks for a two-compartment system.(a) Networks with two control loops. (b) Networks with three control loops. The circles marked with “S” and “D” denote stem and differentiated cells respectively. The two cell fate decisions are marked as “div” for divisions and “diff” for differentiation. Positive and negative bow-shaped arrows denote control loops.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3760876&req=5

pone-0072847-g002: Minimal regulatory networks for a two-compartment system.(a) Networks with two control loops. (b) Networks with three control loops. The circles marked with “S” and “D” denote stem and differentiated cells respectively. The two cell fate decisions are marked as “div” for divisions and “diff” for differentiation. Positive and negative bow-shaped arrows denote control loops.
Mentions: In accordance with the first two observations listed above, we can identify the most minimalistic control mechanisms compatible with stability. They only include two controls, and are depicted in figure 2(a). There, we present the self-renewing cell lineage as a sequence of two decisions: a division decision of a stem cell, followed by a differentiation decision (which, if positive, results in the production of two differentiated cells). The positive and negative bow-shaped arrows represent control loops. They originate in the respective populations exerting the control. The first minimal control pattern (considered in [58], [61]) contains a negative control of stem cell divisions, e.g. as a result of contact inhibition, and a negative control of differentiation decisions from downstream (the more differentiated cells there are in the system, the less likely the stem cells will be to differentiate). The second minimal control contains a negative regulation of divisions by differentiated cells (which could also be a type of “crowd-control”), and a positive regulation of differentiation by the stem cells. The latter control loop could be a result of a self-renewal-promoting factor being secreted by a stem cell niche, in which case the more stem cells there are, the less likely each of them will self-renew, resulting in a higher differentiating probability.

Bottom Line: The feedback can be positive or negative in nature.Some of the control mechanisms that we find have been proposed before, but most of them are new, and we describe evidence for their existence in data that have been previously published.By specifying the types of feedback interactions that can maintain homeostasis, our mathematical analysis can be used as a guide to experimentally zero in on the exact molecular mechanisms in specific tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Mathematics, University of California Irvine, Irvine, California, United States of America.

ABSTRACT
Identifying the exact regulatory circuits that can stably maintain tissue homeostasis is critical for our basic understanding of multicellular organisms, and equally critical for identifying how tumors circumvent this regulation, thus providing targets for treatment. Despite great strides in the understanding of the molecular components of stem-cell regulation, the overall mechanisms orchestrating tissue homeostasis are still far from being understood. Typically, tissue contains the stem cells, transit amplifying cells, and terminally differentiated cells. Each of these cell types can potentially secrete regulatory factors and/or respond to factors secreted by other types. The feedback can be positive or negative in nature. This gives rise to a bewildering array of possible mechanisms that drive tissue regulation. In this paper, we propose a novel method of studying stem cell lineage regulation, and identify possible numbers, types, and directions of control loops that are compatible with stability, keep the variance low, and possess a certain degree of robustness. For example, there are exactly two minimal (two-loop) control networks that can regulate two-compartment (stem and differentiated cell) tissues, and 20 such networks in three-compartment tissues. If division and differentiation decisions are coupled, then there must be a negative control loop regulating divisions of stem cells (e.g. by means of contact inhibition). While this mechanism is associated with the highest robustness, there could be systems that maintain stability by means of positive divisions control, coupled with specific types of differentiation control. Some of the control mechanisms that we find have been proposed before, but most of them are new, and we describe evidence for their existence in data that have been previously published. By specifying the types of feedback interactions that can maintain homeostasis, our mathematical analysis can be used as a guide to experimentally zero in on the exact molecular mechanisms in specific tissues.

Show MeSH
Related in: MedlinePlus