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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.


Downward Paneth cell migration is critical for the stability of stem crypt.Panel A) Snapshots of typical crypts at Day 10 for four models. Color code for Panel A: stem cell (red), Paneth cell (green), enterocytes (blue) and Goblet cell (yellow). In all cases, Paneth cell migration is deleted so that they are subject only to the natural proliferative pressures. Model 1) Only the global Wnt gradient is present. Model 2) In addition to the global Wnt gradient, local Wnt production is included at the 100% level. Model 3) BMP inhibition of proliferation is added to Model 2. Model 4) Global Wnt and BMP gradients along with local Wnt production at the 200% level are included. Panel B) Results of an ensemble of 10 simulations for each model, niche height is reported at different times. Note that for models 1–3, stem cells are confined to the crypt base. In model 4 however, the stem cell population expands to reach the top of the crypt. In all cases, the Paneth cell population expands to the top of the crypt due to the lack of active migration. The provided color code indicates the model considered. Panel C) Spatial density of stem and Paneth cell along the z-axis at day 10. Black lines represent the populations for a control model with Paneth migration included (with 100% Wnt production and the BMP inhibition included) and the remaining curves are color coded as in (B). Panel D) Niche height as a function of different local Wnt production rates (100–400%) with reduced stem cell lifetime considered. Quasi steady state is reached for low local Wnt production rate (100–200%) while unconstrained expansion is observed for 300–400%. Panel E-F) Niche height as a function of different local Wnt production rates with reduced (E) and strengthened (F) drag force considered. The niche is stable for all cases with reduced (0.3X) drag. For enlarged (3X) drag, crypts are stable only for small local Wnt production rate (100–200%).
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pcbi.1004285.g004: Downward Paneth cell migration is critical for the stability of stem crypt.Panel A) Snapshots of typical crypts at Day 10 for four models. Color code for Panel A: stem cell (red), Paneth cell (green), enterocytes (blue) and Goblet cell (yellow). In all cases, Paneth cell migration is deleted so that they are subject only to the natural proliferative pressures. Model 1) Only the global Wnt gradient is present. Model 2) In addition to the global Wnt gradient, local Wnt production is included at the 100% level. Model 3) BMP inhibition of proliferation is added to Model 2. Model 4) Global Wnt and BMP gradients along with local Wnt production at the 200% level are included. Panel B) Results of an ensemble of 10 simulations for each model, niche height is reported at different times. Note that for models 1–3, stem cells are confined to the crypt base. In model 4 however, the stem cell population expands to reach the top of the crypt. In all cases, the Paneth cell population expands to the top of the crypt due to the lack of active migration. The provided color code indicates the model considered. Panel C) Spatial density of stem and Paneth cell along the z-axis at day 10. Black lines represent the populations for a control model with Paneth migration included (with 100% Wnt production and the BMP inhibition included) and the remaining curves are color coded as in (B). Panel D) Niche height as a function of different local Wnt production rates (100–400%) with reduced stem cell lifetime considered. Quasi steady state is reached for low local Wnt production rate (100–200%) while unconstrained expansion is observed for 300–400%. Panel E-F) Niche height as a function of different local Wnt production rates with reduced (E) and strengthened (F) drag force considered. The niche is stable for all cases with reduced (0.3X) drag. For enlarged (3X) drag, crypts are stable only for small local Wnt production rate (100–200%).

Mentions: To determine the role of this migration in crypt homeostasis, we consider four separate models (Fig 4A–4C). In each case, the base model with Paneth migration leads to stable niche formation, and we consider here how deletion of that migration influences homeostasis. In the first, Paneth derived Wnt and BMP signaling are not considered, so that the external Wnt gradient is solely responsible for homeostasis. Under this circumstance, abrogating this downward motion leads to Paneth cells interspersed along the crypt walls, but leaves the stem cell niche unchanged. When Paneth cell derived Wnt is included at low levels (model 2), removal of directed Paneth motion has the same effect. Inclusion of BMP signaling (model 3) again leads to the same results. In the final model (model 4), both BMP signaling and Paneth derived Wnt at levels that are sufficient for redundancy (200%) are included. In this case we see that loss of downward migration leads to expansion of both stem and progenitor cell populations and the niche takes over the 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)

Downward Paneth cell migration is critical for the stability of stem crypt.Panel A) Snapshots of typical crypts at Day 10 for four models. Color code for Panel A: stem cell (red), Paneth cell (green), enterocytes (blue) and Goblet cell (yellow). In all cases, Paneth cell migration is deleted so that they are subject only to the natural proliferative pressures. Model 1) Only the global Wnt gradient is present. Model 2) In addition to the global Wnt gradient, local Wnt production is included at the 100% level. Model 3) BMP inhibition of proliferation is added to Model 2. Model 4) Global Wnt and BMP gradients along with local Wnt production at the 200% level are included. Panel B) Results of an ensemble of 10 simulations for each model, niche height is reported at different times. Note that for models 1–3, stem cells are confined to the crypt base. In model 4 however, the stem cell population expands to reach the top of the crypt. In all cases, the Paneth cell population expands to the top of the crypt due to the lack of active migration. The provided color code indicates the model considered. Panel C) Spatial density of stem and Paneth cell along the z-axis at day 10. Black lines represent the populations for a control model with Paneth migration included (with 100% Wnt production and the BMP inhibition included) and the remaining curves are color coded as in (B). Panel D) Niche height as a function of different local Wnt production rates (100–400%) with reduced stem cell lifetime considered. Quasi steady state is reached for low local Wnt production rate (100–200%) while unconstrained expansion is observed for 300–400%. Panel E-F) Niche height as a function of different local Wnt production rates with reduced (E) and strengthened (F) drag force considered. The niche is stable for all cases with reduced (0.3X) drag. For enlarged (3X) drag, crypts are stable only for small local Wnt production rate (100–200%).
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pcbi.1004285.g004: Downward Paneth cell migration is critical for the stability of stem crypt.Panel A) Snapshots of typical crypts at Day 10 for four models. Color code for Panel A: stem cell (red), Paneth cell (green), enterocytes (blue) and Goblet cell (yellow). In all cases, Paneth cell migration is deleted so that they are subject only to the natural proliferative pressures. Model 1) Only the global Wnt gradient is present. Model 2) In addition to the global Wnt gradient, local Wnt production is included at the 100% level. Model 3) BMP inhibition of proliferation is added to Model 2. Model 4) Global Wnt and BMP gradients along with local Wnt production at the 200% level are included. Panel B) Results of an ensemble of 10 simulations for each model, niche height is reported at different times. Note that for models 1–3, stem cells are confined to the crypt base. In model 4 however, the stem cell population expands to reach the top of the crypt. In all cases, the Paneth cell population expands to the top of the crypt due to the lack of active migration. The provided color code indicates the model considered. Panel C) Spatial density of stem and Paneth cell along the z-axis at day 10. Black lines represent the populations for a control model with Paneth migration included (with 100% Wnt production and the BMP inhibition included) and the remaining curves are color coded as in (B). Panel D) Niche height as a function of different local Wnt production rates (100–400%) with reduced stem cell lifetime considered. Quasi steady state is reached for low local Wnt production rate (100–200%) while unconstrained expansion is observed for 300–400%. Panel E-F) Niche height as a function of different local Wnt production rates with reduced (E) and strengthened (F) drag force considered. The niche is stable for all cases with reduced (0.3X) drag. For enlarged (3X) drag, crypts are stable only for small local Wnt production rate (100–200%).
Mentions: To determine the role of this migration in crypt homeostasis, we consider four separate models (Fig 4A–4C). In each case, the base model with Paneth migration leads to stable niche formation, and we consider here how deletion of that migration influences homeostasis. In the first, Paneth derived Wnt and BMP signaling are not considered, so that the external Wnt gradient is solely responsible for homeostasis. Under this circumstance, abrogating this downward motion leads to Paneth cells interspersed along the crypt walls, but leaves the stem cell niche unchanged. When Paneth cell derived Wnt is included at low levels (model 2), removal of directed Paneth motion has the same effect. Inclusion of BMP signaling (model 3) again leads to the same results. In the final model (model 4), both BMP signaling and Paneth derived Wnt at levels that are sufficient for redundancy (200%) are included. In this case we see that loss of downward migration leads to expansion of both stem and progenitor cell populations and the niche takes over the 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.