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The Interplay between Wnt Mediated Expansion and Negative Regulation of Growth Promotes Robust Intestinal Crypt Structure and Homeostasis.

Du H, Nie Q, Holmes WR - PLoS Comput. Biol. (2015)

Bottom Line: This model builds on the sub-cellular element method to account for the three-dimensional structure of the crypt, external regulation by Wnt and BMP, internal regulation by Notch signaling, as well as regulation by internally generated diffusible signals.Further results also point to a new hypothesis for the role of Ephrin mediated motility of Paneth cells, specifically that it is required to constrain niche expansion and maintain the crypt's spatial structure.Combined, these provide an alternative view of crypt homeostasis where the niche is in a constant state of expansion and the spatial structure of the crypt arises as a balance between this expansion and the action of various sources of negative regulation that hold it in check.

View Article: PubMed Central - PubMed

Affiliation: Center for Complex Biological Systems and Department of Mathematics, University of California Irvine, Irvine, California, United States of America.

ABSTRACT
The epithelium of the small intestinal crypt, which has a vital role in protecting the underlying tissue from the harsh intestinal environment, is completely renewed every 4-5 days by a small pool of stem cells at the base of each crypt. How is this renewal controlled and homeostasis maintained, particularly given the rapid nature of this process? Here, based on the recent observations from in vitro "mini gut" studies, we use a hybrid stochastic model of the crypt to investigate how exogenous niche signaling (from Wnt and BMP) combines with auto-regulation to promote homeostasis. This model builds on the sub-cellular element method to account for the three-dimensional structure of the crypt, external regulation by Wnt and BMP, internal regulation by Notch signaling, as well as regulation by internally generated diffusible signals. Results show that Paneth cell derived Wnt signals, which have been observed experimentally to sustain crypts in cultured organs, have a dramatically different influence on niche dynamics than does mesenchyme derived Wnt. While this signaling can indeed act as a redundant backup to the exogenous gradient, it introduces a positive feedback that destabilizes the niche and causes its uncontrolled expansion. We find that in this setting, BMP has a critical role in constraining this expansion, consistent with observations that its removal leads to crypt fission. Further results also point to a new hypothesis for the role of Ephrin mediated motility of Paneth cells, specifically that it is required to constrain niche expansion and maintain the crypt's spatial structure. Combined, these provide an alternative view of crypt homeostasis where the niche is in a constant state of expansion and the spatial structure of the crypt arises as a balance between this expansion and the action of various sources of negative regulation that hold it in check.

No MeSH data available.


Influence of signaling noise on niche dynamics and stability.Plot of stem cell niche height at steady state as a function of Wnt production rate and the amplitude of imposed noise (σ). Noise levels for the exogenous Wnt and BMP gradients are considered to be similar, so in each case we consider each to have noise amplitude of 0, 0.1, 0.2, and 0.4 respectively. Mean and standard deviation over an ensemble of 10 simulations at each production level and noise amplitude is reported. Cases where the bar extends to the top indicate the niche is unstable and expands to occupy the entire crypt.
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pcbi.1004285.g006: Influence of signaling noise on niche dynamics and stability.Plot of stem cell niche height at steady state as a function of Wnt production rate and the amplitude of imposed noise (σ). Noise levels for the exogenous Wnt and BMP gradients are considered to be similar, so in each case we consider each to have noise amplitude of 0, 0.1, 0.2, and 0.4 respectively. Mean and standard deviation over an ensemble of 10 simulations at each production level and noise amplitude is reported. Cases where the bar extends to the top indicate the niche is unstable and expands to occupy the entire crypt.

Mentions: Simulation results indicate that as expected, more noise leads to a higher degree of variation in the size of the stem cell niche; the standard deviation bars become larger in Fig 6 as noise amplitude increases. Additionally, there is a general trend that increased noise amplitude leads to a larger niche. However, this expansion is marginal and for moderate Wnt production rates and noise levels (e.g. 200% with σ = 0–0.2), this noise has little influence on the niche. Surprisingly we find that under more extreme circumstances (both high noise levels and Wnt production rates), that noise has a profound influence on dynamics. Consider the 400% Wnt production rate in Fig 6. When noise levels are low, the stem cell niche expands, but remains stable. When noise levels are further increased however, that expansion becomes uncontrolled and the niche takes over the entire crypt. Thus noise at sufficiently high levels, coupled with high Wnt production rates, can destabilize an otherwise stable crypt.


The Interplay between Wnt Mediated Expansion and Negative Regulation of Growth Promotes Robust Intestinal Crypt Structure and Homeostasis.

Du H, Nie Q, Holmes WR - PLoS Comput. Biol. (2015)

Influence of signaling noise on niche dynamics and stability.Plot of stem cell niche height at steady state as a function of Wnt production rate and the amplitude of imposed noise (σ). Noise levels for the exogenous Wnt and BMP gradients are considered to be similar, so in each case we consider each to have noise amplitude of 0, 0.1, 0.2, and 0.4 respectively. Mean and standard deviation over an ensemble of 10 simulations at each production level and noise amplitude is reported. Cases where the bar extends to the top indicate the niche is unstable and expands to occupy the entire crypt.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543550&req=5

pcbi.1004285.g006: Influence of signaling noise on niche dynamics and stability.Plot of stem cell niche height at steady state as a function of Wnt production rate and the amplitude of imposed noise (σ). Noise levels for the exogenous Wnt and BMP gradients are considered to be similar, so in each case we consider each to have noise amplitude of 0, 0.1, 0.2, and 0.4 respectively. Mean and standard deviation over an ensemble of 10 simulations at each production level and noise amplitude is reported. Cases where the bar extends to the top indicate the niche is unstable and expands to occupy the entire crypt.
Mentions: Simulation results indicate that as expected, more noise leads to a higher degree of variation in the size of the stem cell niche; the standard deviation bars become larger in Fig 6 as noise amplitude increases. Additionally, there is a general trend that increased noise amplitude leads to a larger niche. However, this expansion is marginal and for moderate Wnt production rates and noise levels (e.g. 200% with σ = 0–0.2), this noise has little influence on the niche. Surprisingly we find that under more extreme circumstances (both high noise levels and Wnt production rates), that noise has a profound influence on dynamics. Consider the 400% Wnt production rate in Fig 6. When noise levels are low, the stem cell niche expands, but remains stable. When noise levels are further increased however, that expansion becomes uncontrolled and the niche takes over the entire crypt. Thus noise at sufficiently high levels, coupled with high Wnt production rates, can destabilize an otherwise stable crypt.

Bottom Line: This model builds on the sub-cellular element method to account for the three-dimensional structure of the crypt, external regulation by Wnt and BMP, internal regulation by Notch signaling, as well as regulation by internally generated diffusible signals.Further results also point to a new hypothesis for the role of Ephrin mediated motility of Paneth cells, specifically that it is required to constrain niche expansion and maintain the crypt's spatial structure.Combined, these provide an alternative view of crypt homeostasis where the niche is in a constant state of expansion and the spatial structure of the crypt arises as a balance between this expansion and the action of various sources of negative regulation that hold it in check.

View Article: PubMed Central - PubMed

Affiliation: Center for Complex Biological Systems and Department of Mathematics, University of California Irvine, Irvine, California, United States of America.

ABSTRACT
The epithelium of the small intestinal crypt, which has a vital role in protecting the underlying tissue from the harsh intestinal environment, is completely renewed every 4-5 days by a small pool of stem cells at the base of each crypt. How is this renewal controlled and homeostasis maintained, particularly given the rapid nature of this process? Here, based on the recent observations from in vitro "mini gut" studies, we use a hybrid stochastic model of the crypt to investigate how exogenous niche signaling (from Wnt and BMP) combines with auto-regulation to promote homeostasis. This model builds on the sub-cellular element method to account for the three-dimensional structure of the crypt, external regulation by Wnt and BMP, internal regulation by Notch signaling, as well as regulation by internally generated diffusible signals. Results show that Paneth cell derived Wnt signals, which have been observed experimentally to sustain crypts in cultured organs, have a dramatically different influence on niche dynamics than does mesenchyme derived Wnt. While this signaling can indeed act as a redundant backup to the exogenous gradient, it introduces a positive feedback that destabilizes the niche and causes its uncontrolled expansion. We find that in this setting, BMP has a critical role in constraining this expansion, consistent with observations that its removal leads to crypt fission. Further results also point to a new hypothesis for the role of Ephrin mediated motility of Paneth cells, specifically that it is required to constrain niche expansion and maintain the crypt's spatial structure. Combined, these provide an alternative view of crypt homeostasis where the niche is in a constant state of expansion and the spatial structure of the crypt arises as a balance between this expansion and the action of various sources of negative regulation that hold it in check.

No MeSH data available.