A constant pool of Lgr5+ intestinal stem cells is required for intestinal homeostasis
Lgr5+ crypt base columnar cells, the operational intestinal stem cells (ISCs), are thought to be dispensable for small intestinal (SI) homeostasis. Using a Lgr5-2A-DTR (diphtheria toxin receptor) model, which ablates Lgr5+ cells with near-complete efficiency and retains endogenous levels of Lgr5 exp...
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sg-ntu-dr.10356-1468642023-03-05T16:50:28Z A constant pool of Lgr5+ intestinal stem cells is required for intestinal homeostasis Tan, Si Hui Phuah, Phyllis Tan, Liang Thing Yada, Swathi Goh, Jasmine Tomaz, Lucian B. Chua, Magdalene Wong, Esther Lee, Bernett Barker, Nick School of Biological Sciences Lee Kong Chian School of Medicine (LKCMedicine) Science::Biological sciences Lgr5 DTR Lgr5+ crypt base columnar cells, the operational intestinal stem cells (ISCs), are thought to be dispensable for small intestinal (SI) homeostasis. Using a Lgr5-2A-DTR (diphtheria toxin receptor) model, which ablates Lgr5+ cells with near-complete efficiency and retains endogenous levels of Lgr5 expression, we show that persistent depletion of Lgr5+ ISCs in fact compromises SI epithelial integrity and reduces epithelial turnover in vivo. In vitro, Lgr5-2A-DTR SI organoids are unable to establish or survive when Lgr5+ ISCs are continuously eliminated by adding DT to the media. However, transient exposure to DT at the start of culture allows organoids to form, and the rate of outgrowth reduces with the increasing length of DT presence. Our results indicate that intestinal homeostasis requires a constant pool of Lgr5+ ISCs, which is supplied by rapidly reprogrammed non-Lgr5+ crypt populations when preexisting Lgr5+ ISCs are ablated. Agency for Science, Technology and Research (A*STAR) National Research Foundation (NRF) Published version The authors thank IMB-IMU and the SBIC-Nikon Imaging Centre staff for imaging assistance; K. Murad for assistance with the experiments; G. Lim for manuscript assistance; and F. de Sauvage for providing the Lgr5-DTR-EGFP mice. N.B. is supported by the Agency for Science, Technology and Research (A ∗ Star) , the Japan Society for the Promotion of Science (JSPS) KAKENHI grant no. 17H01399 , and the National Research Foundation Singapore (Investigatorship Program award no. NRF-NRF12017-03 ). 2021-03-12T04:23:52Z 2021-03-12T04:23:52Z 2021 Journal Article Tan, S. H., Phuah, P., Tan, L. T., Yada, S., Goh, J., Tomaz, L. B., Chua, M., Wong, E., Lee, B. & Barker, N. (2021). A constant pool of Lgr5+ intestinal stem cells is required for intestinal homeostasis. Cell Reports, 34(4). https://dx.doi.org/10.1016/j.celrep.2020.108633 2211-1247 0000-0002-0809-0085 https://hdl.handle.net/10356/146864 10.1016/j.celrep.2020.108633 33503423 2-s2.0-85099866335 4 34 en NRF-NRF12017-03 Cell Reports © 2020 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/4.0/). application/pdf |
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Science::Biological sciences Lgr5 DTR Tan, Si Hui Phuah, Phyllis Tan, Liang Thing Yada, Swathi Goh, Jasmine Tomaz, Lucian B. Chua, Magdalene Wong, Esther Lee, Bernett Barker, Nick A constant pool of Lgr5+ intestinal stem cells is required for intestinal homeostasis |
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Lgr5+ crypt base columnar cells, the operational intestinal stem cells (ISCs), are thought to be dispensable for small intestinal (SI) homeostasis. Using a Lgr5-2A-DTR (diphtheria toxin receptor) model, which ablates Lgr5+ cells with near-complete efficiency and retains endogenous levels of Lgr5 expression, we show that persistent depletion of Lgr5+ ISCs in fact compromises SI epithelial integrity and reduces epithelial turnover in vivo. In vitro, Lgr5-2A-DTR SI organoids are unable to establish or survive when Lgr5+ ISCs are continuously eliminated by adding DT to the media. However, transient exposure to DT at the start of culture allows organoids to form, and the rate of outgrowth reduces with the increasing length of DT presence. Our results indicate that intestinal homeostasis requires a constant pool of Lgr5+ ISCs, which is supplied by rapidly reprogrammed non-Lgr5+ crypt populations when preexisting Lgr5+ ISCs are ablated. |
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School of Biological Sciences |
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School of Biological Sciences Tan, Si Hui Phuah, Phyllis Tan, Liang Thing Yada, Swathi Goh, Jasmine Tomaz, Lucian B. Chua, Magdalene Wong, Esther Lee, Bernett Barker, Nick |
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Article |
author |
Tan, Si Hui Phuah, Phyllis Tan, Liang Thing Yada, Swathi Goh, Jasmine Tomaz, Lucian B. Chua, Magdalene Wong, Esther Lee, Bernett Barker, Nick |
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Tan, Si Hui |
title |
A constant pool of Lgr5+ intestinal stem cells is required for intestinal homeostasis |
title_short |
A constant pool of Lgr5+ intestinal stem cells is required for intestinal homeostasis |
title_full |
A constant pool of Lgr5+ intestinal stem cells is required for intestinal homeostasis |
title_fullStr |
A constant pool of Lgr5+ intestinal stem cells is required for intestinal homeostasis |
title_full_unstemmed |
A constant pool of Lgr5+ intestinal stem cells is required for intestinal homeostasis |
title_sort |
constant pool of lgr5+ intestinal stem cells is required for intestinal homeostasis |
publishDate |
2021 |
url |
https://hdl.handle.net/10356/146864 |
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1759857642588602368 |