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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.


A schematic illustration of the crypt’s structure and cell lineage classification.Panel A) A cartoon of the intestinal crypt and the relative location of cells of different lineages. Panel B) A diagram of cell lineages. Stem cells give rise to terminally differentiated enterocytes, Goblet and Paneth cells, depending jointly on Wnt concentration as well as Notch expression of that cell’s neighbors. Only Paneth cells undergo apoptosis, since Goblet cells and enterocytes naturally undergo anoikis upon reaching the top of the crypt.
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pcbi.1004285.g001: A schematic illustration of the crypt’s structure and cell lineage classification.Panel A) A cartoon of the intestinal crypt and the relative location of cells of different lineages. Panel B) A diagram of cell lineages. Stem cells give rise to terminally differentiated enterocytes, Goblet and Paneth cells, depending jointly on Wnt concentration as well as Notch expression of that cell’s neighbors. Only Paneth cells undergo apoptosis, since Goblet cells and enterocytes naturally undergo anoikis upon reaching the top of the crypt.

Mentions: Four primary cell types are considered: stem, Paneth, enterocyte, and Goblet. The former two are well known to occupy the base of the crypt while the latter two comprise the upper crypt epithelium (Fig 1A). Since we are primarily interested in how signaling in the stem cell niche influences crypt dynamics and stability, we simplify the system by assuming only stem cells are proliferative and do not include the transient period during which enterocytes and Goblet cells further up the crypt divide. Following a previous study [42], we assume Wnt- and Notch-signaling jointly regulate fate specification (Fig 1B). For both pathways, we assume cells above or below the threshold (THNotch for Notch and THWnt for Wnt) take different fates. INotch denotes the notch activation level of a cell, which is determined by the activation of its neighbors. IWnt represents the Wnt level that a cell is exposed to, which is the sum of contributions from the external Wnt gradient and the Wnt produced by nearby Paneth cells. Fig 1B indicates the combination of these signaling levels that determine each cell’s fate. As in [42], we assume that cells can reversibly transition between Goblet and enterocytes fates, depending on Notch levels. Paneth cells are further assumed to terminally differentiate, after which they enter a long-lived quiescent state.


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)

A schematic illustration of the crypt’s structure and cell lineage classification.Panel A) A cartoon of the intestinal crypt and the relative location of cells of different lineages. Panel B) A diagram of cell lineages. Stem cells give rise to terminally differentiated enterocytes, Goblet and Paneth cells, depending jointly on Wnt concentration as well as Notch expression of that cell’s neighbors. Only Paneth cells undergo apoptosis, since Goblet cells and enterocytes naturally undergo anoikis upon reaching the top of the crypt.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1004285.g001: A schematic illustration of the crypt’s structure and cell lineage classification.Panel A) A cartoon of the intestinal crypt and the relative location of cells of different lineages. Panel B) A diagram of cell lineages. Stem cells give rise to terminally differentiated enterocytes, Goblet and Paneth cells, depending jointly on Wnt concentration as well as Notch expression of that cell’s neighbors. Only Paneth cells undergo apoptosis, since Goblet cells and enterocytes naturally undergo anoikis upon reaching the top of the crypt.
Mentions: Four primary cell types are considered: stem, Paneth, enterocyte, and Goblet. The former two are well known to occupy the base of the crypt while the latter two comprise the upper crypt epithelium (Fig 1A). Since we are primarily interested in how signaling in the stem cell niche influences crypt dynamics and stability, we simplify the system by assuming only stem cells are proliferative and do not include the transient period during which enterocytes and Goblet cells further up the crypt divide. Following a previous study [42], we assume Wnt- and Notch-signaling jointly regulate fate specification (Fig 1B). For both pathways, we assume cells above or below the threshold (THNotch for Notch and THWnt for Wnt) take different fates. INotch denotes the notch activation level of a cell, which is determined by the activation of its neighbors. IWnt represents the Wnt level that a cell is exposed to, which is the sum of contributions from the external Wnt gradient and the Wnt produced by nearby Paneth cells. Fig 1B indicates the combination of these signaling levels that determine each cell’s fate. As in [42], we assume that cells can reversibly transition between Goblet and enterocytes fates, depending on Notch levels. Paneth cells are further assumed to terminally differentiate, after which they enter a long-lived quiescent state.

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.