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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 three-compartment system with three control loops.(a) Left: the 7 networks containing (modifications of) the first pattern of figure 2(a). Right: the 7 networks containing (modifications of) the second pattern of figure 2(a). (b) The remaining 6 networks. Notations are similar to those of figure 2, with “I” denoting the intermediate cell type.
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pone-0072847-g005: Minimal regulatory networks for a three-compartment system with three control loops.(a) Left: the 7 networks containing (modifications of) the first pattern of figure 2(a). Right: the 7 networks containing (modifications of) the second pattern of figure 2(a). (b) The remaining 6 networks. Notations are similar to those of figure 2, with “I” denoting the intermediate cell type.

Mentions: There are exactly 20 different minimal control types (that is, controls containing exactly three loops), see figure 5. 16 of them have different topology, and 4 more have repeated topology but a different sign arrangement, see the 4 control patterns on the right of figure 5(b). These 20 patterns are the three-compartment equivalent of the two minimal patterns found for the two-compartment model.


Principles of regulation of self-renewing cell lineages.

Komarova NL - PLoS ONE (2013)

Minimal regulatory networks for a three-compartment system with three control loops.(a) Left: the 7 networks containing (modifications of) the first pattern of figure 2(a). Right: the 7 networks containing (modifications of) the second pattern of figure 2(a). (b) The remaining 6 networks. Notations are similar to those of figure 2, with “I” denoting the intermediate cell type.
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Related In: Results  -  Collection

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

pone-0072847-g005: Minimal regulatory networks for a three-compartment system with three control loops.(a) Left: the 7 networks containing (modifications of) the first pattern of figure 2(a). Right: the 7 networks containing (modifications of) the second pattern of figure 2(a). (b) The remaining 6 networks. Notations are similar to those of figure 2, with “I” denoting the intermediate cell type.
Mentions: There are exactly 20 different minimal control types (that is, controls containing exactly three loops), see figure 5. 16 of them have different topology, and 4 more have repeated topology but a different sign arrangement, see the 4 control patterns on the right of figure 5(b). These 20 patterns are the three-compartment equivalent of the two minimal patterns found for the two-compartment model.

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