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Enteroendocrine Progenitor Cell–Enriched miR-7 Regulates Intestinal Epithelial Proliferation in an Xiap-Dependent Manner
The enteroendocrine cell (EEC) lineage is important for intestinal homeostasis. It was recently shown that EEC progenitors contribute to intestinal epithelial growth and renewal, but the underlying mechanisms remain poorly understood. MicroRNAs are under-explored along the entire EEC lineage traject...
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Published in: | Cellular and molecular gastroenterology and hepatology 2020-01, Vol.9 (3), p.447-464 |
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creator | Singh, Ajeet P. Hung, Yu-Han Shanahan, Michael T. Kanke, Matt Bonfini, Alessandro Dame, Michael K. Biraud, Mandy Peck, Bailey C.E. Oyesola, Oyebola O. Freund, John M. Cubitt, Rebecca L. Curry, Ennessa G. Gonzalez, Liara M. Bewick, Gavin A. Tait-Wojno, Elia D. Kurpios, Natasza A. Ding, Shengli Spence, Jason R. Dekaney, Christopher M. Buchon, Nicolas Sethupathy, Praveen |
description | The enteroendocrine cell (EEC) lineage is important for intestinal homeostasis. It was recently shown that EEC progenitors contribute to intestinal epithelial growth and renewal, but the underlying mechanisms remain poorly understood. MicroRNAs are under-explored along the entire EEC lineage trajectory, and comparatively little is known about their contributions to intestinal homeostasis.
We leverage unbiased sequencing and eight different mouse models and sorting methods to identify microRNAs enriched along the EEC lineage trajectory. We further characterize the functional role of EEC progenitor-enriched miRNA, miR-7, by in vivo dietary study as well as ex vivo enteroid in mice.
First, we demonstrate that miR-7 is highly enriched across the entire EEC lineage trajectory and is the most enriched miRNA in EEC progenitors relative to Lgr5+ intestinal stem cells. Next, we show in vivo that in EEC progenitors miR-7 is dramatically suppressed under dietary conditions that favor crypt division and suppress EEC abundance. We then demonstrate by functional assays in mouse enteroids that miR-7 exerts robust control of growth, as determined by budding (proxy for crypt division), EdU and PH3 staining, and likely regulates EEC abundance also. Finally, we show by single-cell RNA sequencing analysis that miR-7 regulates Xiap in progenitor/stem cells and we demonstrate in enteroids that the effects of miR-7 on mouse enteroid growth depend in part on Xiap and Egfr signaling.
This study demonstrates for the first time that EEC progenitor cell-enriched miR-7 is altered by dietary perturbations and that it regulates growth in enteroids via intact Xiap and Egfr signaling.
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doi_str_mv | 10.1016/j.jcmgh.2019.11.001 |
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We leverage unbiased sequencing and eight different mouse models and sorting methods to identify microRNAs enriched along the EEC lineage trajectory. We further characterize the functional role of EEC progenitor-enriched miRNA, miR-7, by in vivo dietary study as well as ex vivo enteroid in mice.
First, we demonstrate that miR-7 is highly enriched across the entire EEC lineage trajectory and is the most enriched miRNA in EEC progenitors relative to Lgr5+ intestinal stem cells. Next, we show in vivo that in EEC progenitors miR-7 is dramatically suppressed under dietary conditions that favor crypt division and suppress EEC abundance. We then demonstrate by functional assays in mouse enteroids that miR-7 exerts robust control of growth, as determined by budding (proxy for crypt division), EdU and PH3 staining, and likely regulates EEC abundance also. Finally, we show by single-cell RNA sequencing analysis that miR-7 regulates Xiap in progenitor/stem cells and we demonstrate in enteroids that the effects of miR-7 on mouse enteroid growth depend in part on Xiap and Egfr signaling.
This study demonstrates for the first time that EEC progenitor cell-enriched miR-7 is altered by dietary perturbations and that it regulates growth in enteroids via intact Xiap and Egfr signaling.
[Display omitted]</description><identifier>ISSN: 2352-345X</identifier><identifier>EISSN: 2352-345X</identifier><identifier>DOI: 10.1016/j.jcmgh.2019.11.001</identifier><identifier>PMID: 31756561</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Cell Lineage - genetics ; Cell Proliferation - genetics ; Cells, Cultured ; Computational Biology ; Enteroendocrine Cells - physiology ; Enteroendocrine Lineage ; Enteroid ; ErbB Receptors - metabolism ; Feeding Behavior - physiology ; Female ; Inhibitor of Apoptosis Proteins - genetics ; Inhibitor of Apoptosis Proteins - metabolism ; Intestinal Mucosa - cytology ; Intestinal Mucosa - physiology ; Male ; Mice ; Mice, Transgenic ; MicroRNAs - metabolism ; miR-7 ; Models, Animal ; Organoids ; Original Research ; Primary Cell Culture ; Proliferation ; RNA-Seq ; Signal Transduction - genetics ; Single-Cell Analysis ; Small Intestine ; Stem Cells - physiology</subject><ispartof>Cellular and molecular gastroenterology and hepatology, 2020-01, Vol.9 (3), p.447-464</ispartof><rights>2020 The Authors</rights><rights>Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.</rights><rights>2020 The Authors 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c459t-6adc7d21add9c47317a51ff5cdd01a6314a69c162b991c3961f8a72b86993efb3</citedby><cites>FETCH-LOGICAL-c459t-6adc7d21add9c47317a51ff5cdd01a6314a69c162b991c3961f8a72b86993efb3</cites><orcidid>0000-0001-6642-8665 ; 0000-0003-3636-8387</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021555/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S2352345X19301560$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,3549,27924,27925,45780,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31756561$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Singh, Ajeet P.</creatorcontrib><creatorcontrib>Hung, Yu-Han</creatorcontrib><creatorcontrib>Shanahan, Michael T.</creatorcontrib><creatorcontrib>Kanke, Matt</creatorcontrib><creatorcontrib>Bonfini, Alessandro</creatorcontrib><creatorcontrib>Dame, Michael K.</creatorcontrib><creatorcontrib>Biraud, Mandy</creatorcontrib><creatorcontrib>Peck, Bailey C.E.</creatorcontrib><creatorcontrib>Oyesola, Oyebola O.</creatorcontrib><creatorcontrib>Freund, John M.</creatorcontrib><creatorcontrib>Cubitt, Rebecca L.</creatorcontrib><creatorcontrib>Curry, Ennessa G.</creatorcontrib><creatorcontrib>Gonzalez, Liara M.</creatorcontrib><creatorcontrib>Bewick, Gavin A.</creatorcontrib><creatorcontrib>Tait-Wojno, Elia D.</creatorcontrib><creatorcontrib>Kurpios, Natasza A.</creatorcontrib><creatorcontrib>Ding, Shengli</creatorcontrib><creatorcontrib>Spence, Jason R.</creatorcontrib><creatorcontrib>Dekaney, Christopher M.</creatorcontrib><creatorcontrib>Buchon, Nicolas</creatorcontrib><creatorcontrib>Sethupathy, Praveen</creatorcontrib><title>Enteroendocrine Progenitor Cell–Enriched miR-7 Regulates Intestinal Epithelial Proliferation in an Xiap-Dependent Manner</title><title>Cellular and molecular gastroenterology and hepatology</title><addtitle>Cell Mol Gastroenterol Hepatol</addtitle><description>The enteroendocrine cell (EEC) lineage is important for intestinal homeostasis. It was recently shown that EEC progenitors contribute to intestinal epithelial growth and renewal, but the underlying mechanisms remain poorly understood. MicroRNAs are under-explored along the entire EEC lineage trajectory, and comparatively little is known about their contributions to intestinal homeostasis.
We leverage unbiased sequencing and eight different mouse models and sorting methods to identify microRNAs enriched along the EEC lineage trajectory. We further characterize the functional role of EEC progenitor-enriched miRNA, miR-7, by in vivo dietary study as well as ex vivo enteroid in mice.
First, we demonstrate that miR-7 is highly enriched across the entire EEC lineage trajectory and is the most enriched miRNA in EEC progenitors relative to Lgr5+ intestinal stem cells. Next, we show in vivo that in EEC progenitors miR-7 is dramatically suppressed under dietary conditions that favor crypt division and suppress EEC abundance. We then demonstrate by functional assays in mouse enteroids that miR-7 exerts robust control of growth, as determined by budding (proxy for crypt division), EdU and PH3 staining, and likely regulates EEC abundance also. Finally, we show by single-cell RNA sequencing analysis that miR-7 regulates Xiap in progenitor/stem cells and we demonstrate in enteroids that the effects of miR-7 on mouse enteroid growth depend in part on Xiap and Egfr signaling.
This study demonstrates for the first time that EEC progenitor cell-enriched miR-7 is altered by dietary perturbations and that it regulates growth in enteroids via intact Xiap and Egfr signaling.
[Display omitted]</description><subject>Animals</subject><subject>Cell Lineage - genetics</subject><subject>Cell Proliferation - genetics</subject><subject>Cells, Cultured</subject><subject>Computational Biology</subject><subject>Enteroendocrine Cells - physiology</subject><subject>Enteroendocrine Lineage</subject><subject>Enteroid</subject><subject>ErbB Receptors - metabolism</subject><subject>Feeding Behavior - physiology</subject><subject>Female</subject><subject>Inhibitor of Apoptosis Proteins - genetics</subject><subject>Inhibitor of Apoptosis Proteins - metabolism</subject><subject>Intestinal Mucosa - cytology</subject><subject>Intestinal Mucosa - physiology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>MicroRNAs - metabolism</subject><subject>miR-7</subject><subject>Models, Animal</subject><subject>Organoids</subject><subject>Original Research</subject><subject>Primary Cell Culture</subject><subject>Proliferation</subject><subject>RNA-Seq</subject><subject>Signal Transduction - genetics</subject><subject>Single-Cell Analysis</subject><subject>Small Intestine</subject><subject>Stem Cells - physiology</subject><issn>2352-345X</issn><issn>2352-345X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9UcFu1DAUjBCIVqVfgIR85JLgl8ROfQAJLQtUKgJVIPVmee2X3bdK7GBnK8Gp_9A_5EvwsqUqF05-kmfmzZspiufAK-AgX22rrR3Xm6rmoCqAinN4VBzXjajLphVXjx_MR8VpSlueEW0nOy6eFkcNdEIKCcfFz6WfMQb0LthIHtmXGNboaQ6RLXAYft3cLn0ku0HHRrosO3aJ691gZkzsPFPTTN4MbDnRvMGB8pgFBuoxmpmCZ-SZ8eyKzFS-wymvQT-zT8Z7jM-KJ70ZEp7evSfFt_fLr4uP5cXnD-eLtxelbYWaS2mc7VwNxjll2y5bNwL6XljnOBjZQGuksiDrlVJgGyWhPzNdvTqTSjXYr5qT4s1Bd9qtRnQ2O4hm0FOk0cQfOhjS__542uh1uNYdr0EIkQVe3gnE8H2XT9YjJZvDMR7DLul6H6cSoNoMbQ5QG0NKEfv7NcD1vji91X-K0_viNIDOtWTWi4cO7zl_a8qA1wcA5pyuCaNOltBbdBTRztoF-u-C3xegrqw</recordid><startdate>20200101</startdate><enddate>20200101</enddate><creator>Singh, Ajeet P.</creator><creator>Hung, Yu-Han</creator><creator>Shanahan, Michael T.</creator><creator>Kanke, Matt</creator><creator>Bonfini, Alessandro</creator><creator>Dame, Michael K.</creator><creator>Biraud, Mandy</creator><creator>Peck, Bailey C.E.</creator><creator>Oyesola, Oyebola O.</creator><creator>Freund, John M.</creator><creator>Cubitt, Rebecca L.</creator><creator>Curry, Ennessa G.</creator><creator>Gonzalez, Liara M.</creator><creator>Bewick, Gavin A.</creator><creator>Tait-Wojno, Elia D.</creator><creator>Kurpios, Natasza A.</creator><creator>Ding, Shengli</creator><creator>Spence, Jason R.</creator><creator>Dekaney, Christopher M.</creator><creator>Buchon, Nicolas</creator><creator>Sethupathy, Praveen</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6642-8665</orcidid><orcidid>https://orcid.org/0000-0003-3636-8387</orcidid></search><sort><creationdate>20200101</creationdate><title>Enteroendocrine Progenitor Cell–Enriched miR-7 Regulates Intestinal Epithelial Proliferation in an Xiap-Dependent Manner</title><author>Singh, Ajeet P. ; Hung, Yu-Han ; Shanahan, Michael T. ; Kanke, Matt ; Bonfini, Alessandro ; Dame, Michael K. ; Biraud, Mandy ; Peck, Bailey C.E. ; Oyesola, Oyebola O. ; Freund, John M. ; Cubitt, Rebecca L. ; Curry, Ennessa G. ; Gonzalez, Liara M. ; Bewick, Gavin A. ; Tait-Wojno, Elia D. ; Kurpios, Natasza A. ; Ding, Shengli ; Spence, Jason R. ; Dekaney, Christopher M. ; Buchon, Nicolas ; Sethupathy, Praveen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c459t-6adc7d21add9c47317a51ff5cdd01a6314a69c162b991c3961f8a72b86993efb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Cell Lineage - genetics</topic><topic>Cell Proliferation - genetics</topic><topic>Cells, Cultured</topic><topic>Computational Biology</topic><topic>Enteroendocrine Cells - physiology</topic><topic>Enteroendocrine Lineage</topic><topic>Enteroid</topic><topic>ErbB Receptors - metabolism</topic><topic>Feeding Behavior - physiology</topic><topic>Female</topic><topic>Inhibitor of Apoptosis Proteins - genetics</topic><topic>Inhibitor of Apoptosis Proteins - metabolism</topic><topic>Intestinal Mucosa - cytology</topic><topic>Intestinal Mucosa - physiology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>MicroRNAs - metabolism</topic><topic>miR-7</topic><topic>Models, Animal</topic><topic>Organoids</topic><topic>Original Research</topic><topic>Primary Cell Culture</topic><topic>Proliferation</topic><topic>RNA-Seq</topic><topic>Signal Transduction - genetics</topic><topic>Single-Cell Analysis</topic><topic>Small Intestine</topic><topic>Stem Cells - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Singh, Ajeet P.</creatorcontrib><creatorcontrib>Hung, Yu-Han</creatorcontrib><creatorcontrib>Shanahan, Michael T.</creatorcontrib><creatorcontrib>Kanke, Matt</creatorcontrib><creatorcontrib>Bonfini, Alessandro</creatorcontrib><creatorcontrib>Dame, Michael K.</creatorcontrib><creatorcontrib>Biraud, Mandy</creatorcontrib><creatorcontrib>Peck, Bailey C.E.</creatorcontrib><creatorcontrib>Oyesola, Oyebola O.</creatorcontrib><creatorcontrib>Freund, John M.</creatorcontrib><creatorcontrib>Cubitt, Rebecca L.</creatorcontrib><creatorcontrib>Curry, Ennessa G.</creatorcontrib><creatorcontrib>Gonzalez, Liara M.</creatorcontrib><creatorcontrib>Bewick, Gavin A.</creatorcontrib><creatorcontrib>Tait-Wojno, Elia D.</creatorcontrib><creatorcontrib>Kurpios, Natasza A.</creatorcontrib><creatorcontrib>Ding, Shengli</creatorcontrib><creatorcontrib>Spence, Jason R.</creatorcontrib><creatorcontrib>Dekaney, Christopher M.</creatorcontrib><creatorcontrib>Buchon, Nicolas</creatorcontrib><creatorcontrib>Sethupathy, Praveen</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cellular and molecular gastroenterology and hepatology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Singh, Ajeet P.</au><au>Hung, Yu-Han</au><au>Shanahan, Michael T.</au><au>Kanke, Matt</au><au>Bonfini, Alessandro</au><au>Dame, Michael K.</au><au>Biraud, Mandy</au><au>Peck, Bailey C.E.</au><au>Oyesola, Oyebola O.</au><au>Freund, John M.</au><au>Cubitt, Rebecca L.</au><au>Curry, Ennessa G.</au><au>Gonzalez, Liara M.</au><au>Bewick, Gavin A.</au><au>Tait-Wojno, Elia D.</au><au>Kurpios, Natasza A.</au><au>Ding, Shengli</au><au>Spence, Jason R.</au><au>Dekaney, Christopher M.</au><au>Buchon, Nicolas</au><au>Sethupathy, Praveen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Enteroendocrine Progenitor Cell–Enriched miR-7 Regulates Intestinal Epithelial Proliferation in an Xiap-Dependent Manner</atitle><jtitle>Cellular and molecular gastroenterology and hepatology</jtitle><addtitle>Cell Mol Gastroenterol Hepatol</addtitle><date>2020-01-01</date><risdate>2020</risdate><volume>9</volume><issue>3</issue><spage>447</spage><epage>464</epage><pages>447-464</pages><issn>2352-345X</issn><eissn>2352-345X</eissn><abstract>The enteroendocrine cell (EEC) lineage is important for intestinal homeostasis. It was recently shown that EEC progenitors contribute to intestinal epithelial growth and renewal, but the underlying mechanisms remain poorly understood. MicroRNAs are under-explored along the entire EEC lineage trajectory, and comparatively little is known about their contributions to intestinal homeostasis.
We leverage unbiased sequencing and eight different mouse models and sorting methods to identify microRNAs enriched along the EEC lineage trajectory. We further characterize the functional role of EEC progenitor-enriched miRNA, miR-7, by in vivo dietary study as well as ex vivo enteroid in mice.
First, we demonstrate that miR-7 is highly enriched across the entire EEC lineage trajectory and is the most enriched miRNA in EEC progenitors relative to Lgr5+ intestinal stem cells. Next, we show in vivo that in EEC progenitors miR-7 is dramatically suppressed under dietary conditions that favor crypt division and suppress EEC abundance. We then demonstrate by functional assays in mouse enteroids that miR-7 exerts robust control of growth, as determined by budding (proxy for crypt division), EdU and PH3 staining, and likely regulates EEC abundance also. Finally, we show by single-cell RNA sequencing analysis that miR-7 regulates Xiap in progenitor/stem cells and we demonstrate in enteroids that the effects of miR-7 on mouse enteroid growth depend in part on Xiap and Egfr signaling.
This study demonstrates for the first time that EEC progenitor cell-enriched miR-7 is altered by dietary perturbations and that it regulates growth in enteroids via intact Xiap and Egfr signaling.
[Display omitted]</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>31756561</pmid><doi>10.1016/j.jcmgh.2019.11.001</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0001-6642-8665</orcidid><orcidid>https://orcid.org/0000-0003-3636-8387</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Cell Lineage - genetics Cell Proliferation - genetics Cells, Cultured Computational Biology Enteroendocrine Cells - physiology Enteroendocrine Lineage Enteroid ErbB Receptors - metabolism Feeding Behavior - physiology Female Inhibitor of Apoptosis Proteins - genetics Inhibitor of Apoptosis Proteins - metabolism Intestinal Mucosa - cytology Intestinal Mucosa - physiology Male Mice Mice, Transgenic MicroRNAs - metabolism miR-7 Models, Animal Organoids Original Research Primary Cell Culture Proliferation RNA-Seq Signal Transduction - genetics Single-Cell Analysis Small Intestine Stem Cells - physiology |
title | Enteroendocrine Progenitor Cell–Enriched miR-7 Regulates Intestinal Epithelial Proliferation in an Xiap-Dependent Manner |
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