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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.


Additional local Wnt production by Paneth cells leads to stem cell niche expansion.Panel A) Ratio of each cell type of a typical crypt when local Wnt production capability is 100% and 150% for each Paneth cell, respectively. Color code for Panel A and Panel B: stem cell (red), Paneth cell (green), enterocytes (blue) and Goblet cell (yellow). Panel B) Snapshots of crypts at day 10 for different local Wnt production levels. Panel C) Plot of niche height as a function of different Wnt production rates at multiple times. Mean and standard deviation of an ensemble of 10 simulations is reported. Cases where the bar extends to the top indicate the niche is unstable and expands to occupy the entire crypt. Panel D) Indication of how the global and local Wnt influence the broad dynamics of the niche. Left column indicates the local Wnt production rates considered. G+L indicates that both global and local, Paneth cell derived Wnt are included while the right (L) column considers the setting where the global Wnt gradient is removed. “Stable” indicates a properly structured, steady state crypt results, “dies” indicates the niche (stem and Paneth cells) is completely lost, while “unstable” indicates the niche undergoes uncontrolled expansion. In no scenario is the niche stable both before and after the removal of the Wnt gradient, indicating in this setting Paneth cell derived Wnt cannot act redundantly.
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pcbi.1004285.g002: Additional local Wnt production by Paneth cells leads to stem cell niche expansion.Panel A) Ratio of each cell type of a typical crypt when local Wnt production capability is 100% and 150% for each Paneth cell, respectively. Color code for Panel A and Panel B: stem cell (red), Paneth cell (green), enterocytes (blue) and Goblet cell (yellow). Panel B) Snapshots of crypts at day 10 for different local Wnt production levels. Panel C) Plot of niche height as a function of different Wnt production rates at multiple times. Mean and standard deviation of an ensemble of 10 simulations is reported. Cases where the bar extends to the top indicate the niche is unstable and expands to occupy the entire crypt. Panel D) Indication of how the global and local Wnt influence the broad dynamics of the niche. Left column indicates the local Wnt production rates considered. G+L indicates that both global and local, Paneth cell derived Wnt are included while the right (L) column considers the setting where the global Wnt gradient is removed. “Stable” indicates a properly structured, steady state crypt results, “dies” indicates the niche (stem and Paneth cells) is completely lost, while “unstable” indicates the niche undergoes uncontrolled expansion. In no scenario is the niche stable both before and after the removal of the Wnt gradient, indicating in this setting Paneth cell derived Wnt cannot act redundantly.

Mentions: Simulations are conducted to determine the influence of this added Wnt signaling. Simulations at four different levels of Paneth derived Wnt production are then conducted (Fig 2). All simulation specifics (e.g. initial conditions) are discussed in Materials and Methods. Results indicate that when the local production rate of Wnt is at or below this base rate (100% level), the niche remains stable. However, when that production rate is raised to a level sufficient to sustain stem-ness of neighboring cells, the niche expands and takes over the entire crypt. Time course data and snapshots of the crypt state at a fixed time (Fig 2A and 2B) clearly show the fraction of stem and Paneth cells increase in time at the expense of the fraction of other differentiated cell types. Additionally, an ensemble of simulations (which averages over the inherent stochasticity of these simulations) in Fig 2C indicate that the height of the niche remains stable for low production rates but grows in time for higher production rates.


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)

Additional local Wnt production by Paneth cells leads to stem cell niche expansion.Panel A) Ratio of each cell type of a typical crypt when local Wnt production capability is 100% and 150% for each Paneth cell, respectively. Color code for Panel A and Panel B: stem cell (red), Paneth cell (green), enterocytes (blue) and Goblet cell (yellow). Panel B) Snapshots of crypts at day 10 for different local Wnt production levels. Panel C) Plot of niche height as a function of different Wnt production rates at multiple times. Mean and standard deviation of an ensemble of 10 simulations is reported. Cases where the bar extends to the top indicate the niche is unstable and expands to occupy the entire crypt. Panel D) Indication of how the global and local Wnt influence the broad dynamics of the niche. Left column indicates the local Wnt production rates considered. G+L indicates that both global and local, Paneth cell derived Wnt are included while the right (L) column considers the setting where the global Wnt gradient is removed. “Stable” indicates a properly structured, steady state crypt results, “dies” indicates the niche (stem and Paneth cells) is completely lost, while “unstable” indicates the niche undergoes uncontrolled expansion. In no scenario is the niche stable both before and after the removal of the Wnt gradient, indicating in this setting Paneth cell derived Wnt cannot act redundantly.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1004285.g002: Additional local Wnt production by Paneth cells leads to stem cell niche expansion.Panel A) Ratio of each cell type of a typical crypt when local Wnt production capability is 100% and 150% for each Paneth cell, respectively. Color code for Panel A and Panel B: stem cell (red), Paneth cell (green), enterocytes (blue) and Goblet cell (yellow). Panel B) Snapshots of crypts at day 10 for different local Wnt production levels. Panel C) Plot of niche height as a function of different Wnt production rates at multiple times. Mean and standard deviation of an ensemble of 10 simulations is reported. Cases where the bar extends to the top indicate the niche is unstable and expands to occupy the entire crypt. Panel D) Indication of how the global and local Wnt influence the broad dynamics of the niche. Left column indicates the local Wnt production rates considered. G+L indicates that both global and local, Paneth cell derived Wnt are included while the right (L) column considers the setting where the global Wnt gradient is removed. “Stable” indicates a properly structured, steady state crypt results, “dies” indicates the niche (stem and Paneth cells) is completely lost, while “unstable” indicates the niche undergoes uncontrolled expansion. In no scenario is the niche stable both before and after the removal of the Wnt gradient, indicating in this setting Paneth cell derived Wnt cannot act redundantly.
Mentions: Simulations are conducted to determine the influence of this added Wnt signaling. Simulations at four different levels of Paneth derived Wnt production are then conducted (Fig 2). All simulation specifics (e.g. initial conditions) are discussed in Materials and Methods. Results indicate that when the local production rate of Wnt is at or below this base rate (100% level), the niche remains stable. However, when that production rate is raised to a level sufficient to sustain stem-ness of neighboring cells, the niche expands and takes over the entire crypt. Time course data and snapshots of the crypt state at a fixed time (Fig 2A and 2B) clearly show the fraction of stem and Paneth cells increase in time at the expense of the fraction of other differentiated cell types. Additionally, an ensemble of simulations (which averages over the inherent stochasticity of these simulations) in Fig 2C indicate that the height of the niche remains stable for low production rates but grows in time for higher production rates.

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.