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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.


Role of BMP on niche homeostasis.Panel A) Niche height as a function of different local Wnt production rates with BMP inhibition of proliferation considered. Mean and standard deviation of an ensemble of 10 simulations is presented. For the 400% production level, expansion continues in time until the niche completely overtakes the crypt. For the 100–300% cases, stability of crypt height has been verified with extended simulations. Panel B) Same as in (A) but with the global Wnt gradient removed. For low production rates, the niche is either completely lost or substantially smaller, but at higher rates (e.g. 200%), the niche height is only slightly impaired, indicating that at these levels the two Wnt sources can function redundantly. In all cases (in B), the niche heights at 5 days post removal represent steady state results.
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pcbi.1004285.g003: Role of BMP on niche homeostasis.Panel A) Niche height as a function of different local Wnt production rates with BMP inhibition of proliferation considered. Mean and standard deviation of an ensemble of 10 simulations is presented. For the 400% production level, expansion continues in time until the niche completely overtakes the crypt. For the 100–300% cases, stability of crypt height has been verified with extended simulations. Panel B) Same as in (A) but with the global Wnt gradient removed. For low production rates, the niche is either completely lost or substantially smaller, but at higher rates (e.g. 200%), the niche height is only slightly impaired, indicating that at these levels the two Wnt sources can function redundantly. In all cases (in B), the niche heights at 5 days post removal represent steady state results.

Mentions: The crypt is again initialized in a canonical configuration and allowed to evolve under the influence of the combination of the global Wnt gradient, the BMP gradient, and Paneth cell derived Wnt. Given the observed influence of local Wnt production rates, different rates are again considered to determine the efficacy of BMP at constraining growth under different niche expansion conditions. Results (Fig 3A) indicate that for moderate levels of Wnt production, BMP is effective at constraining niche expansion and maintaining homeostasis. Interestingly, with this form of repression, the crypt structure is highly robust and the niche size is insensitive to Wnt production rates. That is, raising the production rate from 100% to 300% of the critical base level has no significant influence on niche height. The exception to this is that at very high levels of Wnt production (400% in Fig 3A), the niche becomes substantially enlarged. These results suggest that BMP inhibition of proliferation is an effective mechanism for repressing crypt expansion and robustly determining the niche size, provided Wnt production rates are not excessively large.


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)

Role of BMP on niche homeostasis.Panel A) Niche height as a function of different local Wnt production rates with BMP inhibition of proliferation considered. Mean and standard deviation of an ensemble of 10 simulations is presented. For the 400% production level, expansion continues in time until the niche completely overtakes the crypt. For the 100–300% cases, stability of crypt height has been verified with extended simulations. Panel B) Same as in (A) but with the global Wnt gradient removed. For low production rates, the niche is either completely lost or substantially smaller, but at higher rates (e.g. 200%), the niche height is only slightly impaired, indicating that at these levels the two Wnt sources can function redundantly. In all cases (in B), the niche heights at 5 days post removal represent steady state results.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4543550&req=5

pcbi.1004285.g003: Role of BMP on niche homeostasis.Panel A) Niche height as a function of different local Wnt production rates with BMP inhibition of proliferation considered. Mean and standard deviation of an ensemble of 10 simulations is presented. For the 400% production level, expansion continues in time until the niche completely overtakes the crypt. For the 100–300% cases, stability of crypt height has been verified with extended simulations. Panel B) Same as in (A) but with the global Wnt gradient removed. For low production rates, the niche is either completely lost or substantially smaller, but at higher rates (e.g. 200%), the niche height is only slightly impaired, indicating that at these levels the two Wnt sources can function redundantly. In all cases (in B), the niche heights at 5 days post removal represent steady state results.
Mentions: The crypt is again initialized in a canonical configuration and allowed to evolve under the influence of the combination of the global Wnt gradient, the BMP gradient, and Paneth cell derived Wnt. Given the observed influence of local Wnt production rates, different rates are again considered to determine the efficacy of BMP at constraining growth under different niche expansion conditions. Results (Fig 3A) indicate that for moderate levels of Wnt production, BMP is effective at constraining niche expansion and maintaining homeostasis. Interestingly, with this form of repression, the crypt structure is highly robust and the niche size is insensitive to Wnt production rates. That is, raising the production rate from 100% to 300% of the critical base level has no significant influence on niche height. The exception to this is that at very high levels of Wnt production (400% in Fig 3A), the niche becomes substantially enlarged. These results suggest that BMP inhibition of proliferation is an effective mechanism for repressing crypt expansion and robustly determining the niche size, provided Wnt production rates are not excessively large.

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.