A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self‐renewal
Abstract The intestinal epithelium is the fastest regenerative tissue in the body, fueled by fast‐cycling stem cells. The number and identity of these dividing and migrating stem cells are maintained by a mosaic pattern at the base of the crypt. How the underlying regulatory scheme manages this dyna...
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Springer Nature
2017-04-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.15252/msb.20167324 |
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| author | Kai‐Yuan Chen Tara Srinivasan Kuei‐Ling Tung Julio M Belmonte Lihua Wang Preetish Kadur Lakshminarasimha Murthy Jiahn Choi Nikolai Rakhilin Sarah King Anastasia Kristine Varanko Mavee Witherspoon Nozomi Nishimura James A Glazier Steven M Lipkin Pengcheng Bu Xiling Shen |
| author_facet | Kai‐Yuan Chen Tara Srinivasan Kuei‐Ling Tung Julio M Belmonte Lihua Wang Preetish Kadur Lakshminarasimha Murthy Jiahn Choi Nikolai Rakhilin Sarah King Anastasia Kristine Varanko Mavee Witherspoon Nozomi Nishimura James A Glazier Steven M Lipkin Pengcheng Bu Xiling Shen |
| author_sort | Kai‐Yuan Chen |
| collection | DOAJ |
| description | Abstract The intestinal epithelium is the fastest regenerative tissue in the body, fueled by fast‐cycling stem cells. The number and identity of these dividing and migrating stem cells are maintained by a mosaic pattern at the base of the crypt. How the underlying regulatory scheme manages this dynamic stem cell niche is not entirely clear. We stimulated intestinal organoids with Notch ligands and inhibitors and discovered that intestinal stem cells employ a positive feedback mechanism via direct Notch binding to the second intron of the Notch1 gene. Inactivation of the positive feedback by CRISPR/Cas9 mutation of the binding sequence alters the mosaic stem cell niche pattern and hinders regeneration in organoids. Dynamical system analysis and agent‐based multiscale stochastic modeling suggest that the positive feedback enhances the robustness of Notch‐mediated niche patterning. This study highlights the importance of feedback mechanisms in spatiotemporal control of the stem cell niche. |
| format | Article |
| id | doaj-art-1b673af1fdcb4bcdaa53740941263cec |
| institution | DOAJ |
| issn | 1744-4292 |
| language | English |
| publishDate | 2017-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-1b673af1fdcb4bcdaa53740941263cec2025-08-20T03:06:36ZengSpringer NatureMolecular Systems Biology1744-42922017-04-0113411610.15252/msb.20167324A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self‐renewalKai‐Yuan Chen0Tara Srinivasan1Kuei‐Ling Tung2Julio M Belmonte3Lihua Wang4Preetish Kadur Lakshminarasimha Murthy5Jiahn Choi6Nikolai Rakhilin7Sarah King8Anastasia Kristine Varanko9Mavee Witherspoon10Nozomi Nishimura11James A Glazier12Steven M Lipkin13Pengcheng Bu14Xiling Shen15School of Electrical and Computer Engineering, Cornell UniversityDepartment of Biomedical Engineering, Cornell UniversityDepartment of Biological and Environmental Engineering, Cornell UniversityBiocomplexity Institute and Department of Physics, Indiana UniversityDepartment of Biomedical Engineering, Duke UniversitySchool of Mechanical Aerospace Engineering, Cornell UniversityDepartment of Biomedical Engineering, Duke UniversitySchool of Electrical and Computer Engineering, Cornell UniversityDepartment of Biomedical Engineering, Cornell UniversityDepartment of Biological and Environmental Engineering, Cornell UniversitySchool of Mechanical Aerospace Engineering, Cornell UniversityDepartment of Biomedical Engineering, Cornell UniversityBiocomplexity Institute and Department of Physics, Indiana UniversityDepartments of Medicine, Genetic Medicine and Surgery, Weill Cornell Medical CollegeDepartment of Biomedical Engineering, Duke UniversitySchool of Electrical and Computer Engineering, Cornell UniversityAbstract The intestinal epithelium is the fastest regenerative tissue in the body, fueled by fast‐cycling stem cells. The number and identity of these dividing and migrating stem cells are maintained by a mosaic pattern at the base of the crypt. How the underlying regulatory scheme manages this dynamic stem cell niche is not entirely clear. We stimulated intestinal organoids with Notch ligands and inhibitors and discovered that intestinal stem cells employ a positive feedback mechanism via direct Notch binding to the second intron of the Notch1 gene. Inactivation of the positive feedback by CRISPR/Cas9 mutation of the binding sequence alters the mosaic stem cell niche pattern and hinders regeneration in organoids. Dynamical system analysis and agent‐based multiscale stochastic modeling suggest that the positive feedback enhances the robustness of Notch‐mediated niche patterning. This study highlights the importance of feedback mechanisms in spatiotemporal control of the stem cell niche.https://doi.org/10.15252/msb.20167324gene editingintestine stem cellNotch signalingorganoidpositive feedback |
| spellingShingle | Kai‐Yuan Chen Tara Srinivasan Kuei‐Ling Tung Julio M Belmonte Lihua Wang Preetish Kadur Lakshminarasimha Murthy Jiahn Choi Nikolai Rakhilin Sarah King Anastasia Kristine Varanko Mavee Witherspoon Nozomi Nishimura James A Glazier Steven M Lipkin Pengcheng Bu Xiling Shen A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self‐renewal Molecular Systems Biology gene editing intestine stem cell Notch signaling organoid positive feedback |
| title | A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self‐renewal |
| title_full | A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self‐renewal |
| title_fullStr | A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self‐renewal |
| title_full_unstemmed | A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self‐renewal |
| title_short | A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self‐renewal |
| title_sort | notch positive feedback in the intestinal stem cell niche is essential for stem cell self renewal |
| topic | gene editing intestine stem cell Notch signaling organoid positive feedback |
| url | https://doi.org/10.15252/msb.20167324 |
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