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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.


Diffusivity and degradation influence stem cell niche stability.Panels A and B show the effect of reducing diffusivity or the strength of local Wnt degradation on niche dynamics. 0.3X and 0.1X each indicate the factor by which the relevant parameter is reduced. In A it is “D” that is reduced while in B, “d” is reduced.
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pcbi.1004285.g005: Diffusivity and degradation influence stem cell niche stability.Panels A and B show the effect of reducing diffusivity or the strength of local Wnt degradation on niche dynamics. 0.3X and 0.1X each indicate the factor by which the relevant parameter is reduced. In A it is “D” that is reduced while in B, “d” is reduced.

Mentions: From this, we see that increasing the rate of either diffusion or decay will reduce the Wnt concentration near the production source. As a result, we would expect either of these manipulations to have the effect of repressing niche expansion, while also reducing the ability of Paneth cells to maintain the niche on their own. Alternatively, we would expect reducing either would promote expansion and simulation results where both manipulations are performed (Fig 5) do show these manipulations promote expansion. Thus, in addition to the production rate of Wnt, its diffusion and degradation also have an important influence on homeostasis. More specifically, these properties determine whether local concentrations (near the source of production) are sufficiently high to sustain the positive feedback between stem and Paneth cells that drives expansion.


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)

Diffusivity and degradation influence stem cell niche stability.Panels A and B show the effect of reducing diffusivity or the strength of local Wnt degradation on niche dynamics. 0.3X and 0.1X each indicate the factor by which the relevant parameter is reduced. In A it is “D” that is reduced while in B, “d” is reduced.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1004285.g005: Diffusivity and degradation influence stem cell niche stability.Panels A and B show the effect of reducing diffusivity or the strength of local Wnt degradation on niche dynamics. 0.3X and 0.1X each indicate the factor by which the relevant parameter is reduced. In A it is “D” that is reduced while in B, “d” is reduced.
Mentions: From this, we see that increasing the rate of either diffusion or decay will reduce the Wnt concentration near the production source. As a result, we would expect either of these manipulations to have the effect of repressing niche expansion, while also reducing the ability of Paneth cells to maintain the niche on their own. Alternatively, we would expect reducing either would promote expansion and simulation results where both manipulations are performed (Fig 5) do show these manipulations promote expansion. Thus, in addition to the production rate of Wnt, its diffusion and degradation also have an important influence on homeostasis. More specifically, these properties determine whether local concentrations (near the source of production) are sufficiently high to sustain the positive feedback between stem and Paneth cells that drives expansion.

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.