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Cell lineages and the logic of proliferative control.

Lander AD, Gokoffski KK, Wan FY, Nie Q, Calof AL - PLoS Biol. (2009)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California, USA. adlander@uci.edu

ABSTRACT
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.

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Experimental Demonstration That GDF11 Regulates p1 and v1OE explants were cultured in various doses of GDF11. At 12 h, BrdU was added for 2 h and then washed out. Explants were fixed at various times after BrdU addition and immunostained for BrdU and NCAM expression.(A–I) Cultures grown in GDF11 concentrations of 0 (A, D, and G), 0.5 (B, E, and H), and 10 (C, F, and I) ng/ml, fixed 18 h after BrdU addition (previous studies have shown that 18 h is sufficient time for INP progeny that become ORNs to express NCAM [39]). NCAM immunofluorescence (green) is shown in (A–C); BrdU immunofluorescence (red) in (D–F); merged images in (G–I). Arrowheads point to examples of BrdU+/NCAM− cells; arrows point to examples of BrdU+/NCAM+ cells.(J) Percentage of BrdU+ cells migrating out of OE explants that had differentiated (acquired NCAM immunoreactivity) by 18 h (black line) or 36 h (blue line), as a function of GDF11 dose. Low doses of GDF11 increase the proportion of INP progeny that differentiate (i.e., p1 decreases). At high dose, the effect reverses, with the NCAM+ fraction falling to near zero at 18 h, but recovering at 36 h. These data are consistent with a slowing of the cell cycle (v1) such that 18 h is not long enough to produce NCAM+ offspring (but 36 h is). This interpretation is consistent with a previous demonstration that high doses of GDF11 reversibly arrest the INP cell cycle [34].(K) Simulation of the experiment in (J) by a model in which GDF11 affects both p1 and v1. Parameters used in the model are consistent with measured proportions of ORNs, INPs, and Mash1+/Sox2+ cells, as well as experimental data on the effects of GDF11 on BrdU pulse-labeling by INPs [34,39,40].
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pbio-1000015-g004: Experimental Demonstration That GDF11 Regulates p1 and v1OE explants were cultured in various doses of GDF11. At 12 h, BrdU was added for 2 h and then washed out. Explants were fixed at various times after BrdU addition and immunostained for BrdU and NCAM expression.(A–I) Cultures grown in GDF11 concentrations of 0 (A, D, and G), 0.5 (B, E, and H), and 10 (C, F, and I) ng/ml, fixed 18 h after BrdU addition (previous studies have shown that 18 h is sufficient time for INP progeny that become ORNs to express NCAM [39]). NCAM immunofluorescence (green) is shown in (A–C); BrdU immunofluorescence (red) in (D–F); merged images in (G–I). Arrowheads point to examples of BrdU+/NCAM− cells; arrows point to examples of BrdU+/NCAM+ cells.(J) Percentage of BrdU+ cells migrating out of OE explants that had differentiated (acquired NCAM immunoreactivity) by 18 h (black line) or 36 h (blue line), as a function of GDF11 dose. Low doses of GDF11 increase the proportion of INP progeny that differentiate (i.e., p1 decreases). At high dose, the effect reverses, with the NCAM+ fraction falling to near zero at 18 h, but recovering at 36 h. These data are consistent with a slowing of the cell cycle (v1) such that 18 h is not long enough to produce NCAM+ offspring (but 36 h is). This interpretation is consistent with a previous demonstration that high doses of GDF11 reversibly arrest the INP cell cycle [34].(K) Simulation of the experiment in (J) by a model in which GDF11 affects both p1 and v1. Parameters used in the model are consistent with measured proportions of ORNs, INPs, and Mash1+/Sox2+ cells, as well as experimental data on the effects of GDF11 on BrdU pulse-labeling by INPs [34,39,40].

Mentions: Figure 4 shows the effect of GDF11 (added to the culture medium 12 h prior to BrdU labeling) on acquisition of NCAM expression by BrdU pulse-labeled cells. In Figure 4J, data for two different “chase” periods are graphed. In the absence of GDF11, about 60% of BrdU-labeled cells become NCAM-positive within 18 h. In the presence of low levels of GDF11, this percentage rises as high as 75%, then falls again at high concentrations of GDF11 to less than 10%.


Cell lineages and the logic of proliferative control.

Lander AD, Gokoffski KK, Wan FY, Nie Q, Calof AL - PLoS Biol. (2009)

Experimental Demonstration That GDF11 Regulates p1 and v1OE explants were cultured in various doses of GDF11. At 12 h, BrdU was added for 2 h and then washed out. Explants were fixed at various times after BrdU addition and immunostained for BrdU and NCAM expression.(A–I) Cultures grown in GDF11 concentrations of 0 (A, D, and G), 0.5 (B, E, and H), and 10 (C, F, and I) ng/ml, fixed 18 h after BrdU addition (previous studies have shown that 18 h is sufficient time for INP progeny that become ORNs to express NCAM [39]). NCAM immunofluorescence (green) is shown in (A–C); BrdU immunofluorescence (red) in (D–F); merged images in (G–I). Arrowheads point to examples of BrdU+/NCAM− cells; arrows point to examples of BrdU+/NCAM+ cells.(J) Percentage of BrdU+ cells migrating out of OE explants that had differentiated (acquired NCAM immunoreactivity) by 18 h (black line) or 36 h (blue line), as a function of GDF11 dose. Low doses of GDF11 increase the proportion of INP progeny that differentiate (i.e., p1 decreases). At high dose, the effect reverses, with the NCAM+ fraction falling to near zero at 18 h, but recovering at 36 h. These data are consistent with a slowing of the cell cycle (v1) such that 18 h is not long enough to produce NCAM+ offspring (but 36 h is). This interpretation is consistent with a previous demonstration that high doses of GDF11 reversibly arrest the INP cell cycle [34].(K) Simulation of the experiment in (J) by a model in which GDF11 affects both p1 and v1. Parameters used in the model are consistent with measured proportions of ORNs, INPs, and Mash1+/Sox2+ cells, as well as experimental data on the effects of GDF11 on BrdU pulse-labeling by INPs [34,39,40].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2628408&req=5

pbio-1000015-g004: Experimental Demonstration That GDF11 Regulates p1 and v1OE explants were cultured in various doses of GDF11. At 12 h, BrdU was added for 2 h and then washed out. Explants were fixed at various times after BrdU addition and immunostained for BrdU and NCAM expression.(A–I) Cultures grown in GDF11 concentrations of 0 (A, D, and G), 0.5 (B, E, and H), and 10 (C, F, and I) ng/ml, fixed 18 h after BrdU addition (previous studies have shown that 18 h is sufficient time for INP progeny that become ORNs to express NCAM [39]). NCAM immunofluorescence (green) is shown in (A–C); BrdU immunofluorescence (red) in (D–F); merged images in (G–I). Arrowheads point to examples of BrdU+/NCAM− cells; arrows point to examples of BrdU+/NCAM+ cells.(J) Percentage of BrdU+ cells migrating out of OE explants that had differentiated (acquired NCAM immunoreactivity) by 18 h (black line) or 36 h (blue line), as a function of GDF11 dose. Low doses of GDF11 increase the proportion of INP progeny that differentiate (i.e., p1 decreases). At high dose, the effect reverses, with the NCAM+ fraction falling to near zero at 18 h, but recovering at 36 h. These data are consistent with a slowing of the cell cycle (v1) such that 18 h is not long enough to produce NCAM+ offspring (but 36 h is). This interpretation is consistent with a previous demonstration that high doses of GDF11 reversibly arrest the INP cell cycle [34].(K) Simulation of the experiment in (J) by a model in which GDF11 affects both p1 and v1. Parameters used in the model are consistent with measured proportions of ORNs, INPs, and Mash1+/Sox2+ cells, as well as experimental data on the effects of GDF11 on BrdU pulse-labeling by INPs [34,39,40].
Mentions: Figure 4 shows the effect of GDF11 (added to the culture medium 12 h prior to BrdU labeling) on acquisition of NCAM expression by BrdU pulse-labeled cells. In Figure 4J, data for two different “chase” periods are graphed. In the absence of GDF11, about 60% of BrdU-labeled cells become NCAM-positive within 18 h. In the presence of low levels of GDF11, this percentage rises as high as 75%, then falls again at high concentrations of GDF11 to less than 10%.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California, USA. adlander@uci.edu

ABSTRACT
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.

Show MeSH