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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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The schematic of cellular decisions and regulation by cell populations.The circles marked with “S” and “D” denote stem and differentiated cells respectively. On the left, a stem cell decision tree is shown, which includes division/senescence decisions as well as proliferation/differentiation decisions. On top right, a differentiated cell decision tree is shown. All the decisions can be controlled by factors produced by the stem cell population and/or differentiated cell population. The control can be negative or positive in each case.
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pone-0072847-g001: The schematic of cellular decisions and regulation by cell populations.The circles marked with “S” and “D” denote stem and differentiated cells respectively. On the left, a stem cell decision tree is shown, which includes division/senescence decisions as well as proliferation/differentiation decisions. On top right, a differentiated cell decision tree is shown. All the decisions can be controlled by factors produced by the stem cell population and/or differentiated cell population. The control can be negative or positive in each case.

Mentions: Which cell divides when and what division type it undergoes must be subject to feedback loops, to assure that the populations sizes do not deviate dangerously from the physiologically desired levels, as a result of random fluctuations [58]. The framework adopted here is depicted schematically in figure 1. It shows the example of a simplified system where only two cell types are present: stem cells and differentiated cells. Each stem cell faces two types of decisions: division/senescence decisions, where it divides with rate , and (upon division) proliferation/differentiation decisions, where it differentiated with probability . Daughter cells die with rate . All the decisions can be controlled by factors produced by the stem cell population and/or differentiated cell population, which is shown schematically by thick arrows. Mathematically this is reflected in the fact that quantities , , and are not constant parameters, but can be functions of the population sizes of different compartments.


Principles of regulation of self-renewing cell lineages.

Komarova NL - PLoS ONE (2013)

The schematic of cellular decisions and regulation by cell populations.The circles marked with “S” and “D” denote stem and differentiated cells respectively. On the left, a stem cell decision tree is shown, which includes division/senescence decisions as well as proliferation/differentiation decisions. On top right, a differentiated cell decision tree is shown. All the decisions can be controlled by factors produced by the stem cell population and/or differentiated cell population. The control can be negative or positive in each case.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0072847-g001: The schematic of cellular decisions and regulation by cell populations.The circles marked with “S” and “D” denote stem and differentiated cells respectively. On the left, a stem cell decision tree is shown, which includes division/senescence decisions as well as proliferation/differentiation decisions. On top right, a differentiated cell decision tree is shown. All the decisions can be controlled by factors produced by the stem cell population and/or differentiated cell population. The control can be negative or positive in each case.
Mentions: Which cell divides when and what division type it undergoes must be subject to feedback loops, to assure that the populations sizes do not deviate dangerously from the physiologically desired levels, as a result of random fluctuations [58]. The framework adopted here is depicted schematically in figure 1. It shows the example of a simplified system where only two cell types are present: stem cells and differentiated cells. Each stem cell faces two types of decisions: division/senescence decisions, where it divides with rate , and (upon division) proliferation/differentiation decisions, where it differentiated with probability . Daughter cells die with rate . All the decisions can be controlled by factors produced by the stem cell population and/or differentiated cell population, which is shown schematically by thick arrows. Mathematically this is reflected in the fact that quantities , , and are not constant parameters, but can be functions of the population sizes of different compartments.

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