Optimality in the Development of Intestinal Crypts
Intestinal crypts in mammals are comprised of long-lived stem cells and shorter-lived progenies. These two populations are maintained in specific proportions during adult life. Here, we investigate the design principles governing the dynamics of these proportions during crypt morphogenesis. Using op...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2014
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| Online Access: | http://hdl.handle.net/1721.1/92250 https://orcid.org/0000-0001-5785-8911 |
| _version_ | 1826188607484854272 |
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| author | Itzkovitz, Shaul Shalev Blat, Irene C. Clevers, Hans van Oudenaarden, Alexander Jacks, Tyler E. van Oudenaarden, Alexander |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Itzkovitz, Shaul Shalev Blat, Irene C. Clevers, Hans van Oudenaarden, Alexander Jacks, Tyler E. van Oudenaarden, Alexander |
| author_sort | Itzkovitz, Shaul Shalev |
| collection | MIT |
| description | Intestinal crypts in mammals are comprised of long-lived stem cells and shorter-lived progenies. These two populations are maintained in specific proportions during adult life. Here, we investigate the design principles governing the dynamics of these proportions during crypt morphogenesis. Using optimal control theory, we show that a proliferation strategy known as a “bang-bang” control minimizes the time to obtain a mature crypt. This strategy consists of a surge of symmetric stem cell divisions, establishing the entire stem cell pool first, followed by a sharp transition to strictly asymmetric stem cell divisions, producing nonstem cells with a delay. We validate these predictions using lineage tracing and single-molecule fluorescence in situ hybridization of intestinal crypts in infant mice, uncovering small crypts that are entirely composed of Lgr5-labeled stem cells, which become a minority as crypts continue to grow. Our approach can be used to uncover similar design principles in other developmental systems. |
| first_indexed | 2024-09-23T08:02:22Z |
| format | Article |
| id | mit-1721.1/92250 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:02:22Z |
| publishDate | 2014 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/922502022-09-30T01:51:39Z Optimality in the Development of Intestinal Crypts Itzkovitz, Shaul Shalev Blat, Irene C. Clevers, Hans van Oudenaarden, Alexander Jacks, Tyler E. van Oudenaarden, Alexander Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Physics Koch Institute for Integrative Cancer Research at MIT Itzkovitz, Shaul Shalev van Oudenaarden, Alexander Blat, Irene C. Jacks, Tyler E. Intestinal crypts in mammals are comprised of long-lived stem cells and shorter-lived progenies. These two populations are maintained in specific proportions during adult life. Here, we investigate the design principles governing the dynamics of these proportions during crypt morphogenesis. Using optimal control theory, we show that a proliferation strategy known as a “bang-bang” control minimizes the time to obtain a mature crypt. This strategy consists of a surge of symmetric stem cell divisions, establishing the entire stem cell pool first, followed by a sharp transition to strictly asymmetric stem cell divisions, producing nonstem cells with a delay. We validate these predictions using lineage tracing and single-molecule fluorescence in situ hybridization of intestinal crypts in infant mice, uncovering small crypts that are entirely composed of Lgr5-labeled stem cells, which become a minority as crypts continue to grow. Our approach can be used to uncover similar design principles in other developmental systems. National Cancer Institute (U.S.). Physical Sciences-Oncology Center (U54CA143874) National Institutes of Health (U.S.). Pioneer Award (1DP1OD003936) National Cancer Institute (U.S.) (Cancer Center Support (Core) Grant P30-CA14051) Machiah Foundation Human Frontier Science Program (Strasbourg, France) Howard Hughes Medical Institute (Gilliam Fellowship) 2014-12-10T16:12:42Z 2014-12-10T16:12:42Z 2012-02 2011-09 Article http://purl.org/eprint/type/JournalArticle 00928674 1097-4172 http://hdl.handle.net/1721.1/92250 Itzkovitz, Shalev, Irene C. Blat, Tyler Jacks, Hans Clevers, and Alexander van Oudenaarden. “Optimality in the Development of Intestinal Crypts.” Cell 148, no. 3 (February 2012): 608–619. © 2012 Elsevier Inc. https://orcid.org/0000-0001-5785-8911 en_US http://dx.doi.org/10.1016/j.cell.2011.12.025 Cell Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Elsevier Elsevier |
| spellingShingle | Itzkovitz, Shaul Shalev Blat, Irene C. Clevers, Hans van Oudenaarden, Alexander Jacks, Tyler E. van Oudenaarden, Alexander Optimality in the Development of Intestinal Crypts |
| title | Optimality in the Development of Intestinal Crypts |
| title_full | Optimality in the Development of Intestinal Crypts |
| title_fullStr | Optimality in the Development of Intestinal Crypts |
| title_full_unstemmed | Optimality in the Development of Intestinal Crypts |
| title_short | Optimality in the Development of Intestinal Crypts |
| title_sort | optimality in the development of intestinal crypts |
| url | http://hdl.handle.net/1721.1/92250 https://orcid.org/0000-0001-5785-8911 |
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