Louis R. Parham , Patrick A. Williams , Kay Katada , Shaneice K. Nettleford , Priya Chatterji , Kofi K. Acheampong , Charles H. Danan , Xianghui Ma , Lauren A. Simon , Kaitlyn E. Naughton , Rei Mizuno , Tatiana Karakasheva , Emily A. McMillan , Kelly A. Whelan , Donita C. Brady , Sydney M. Shaffer , Kathryn E. Hamilton
{"title":"IGF2BP1/IMP1缺失可通过调节MAP1LC3B增强面干细胞状态","authors":"Louis R. Parham , Patrick A. Williams , Kay Katada , Shaneice K. Nettleford , Priya Chatterji , Kofi K. Acheampong , Charles H. Danan , Xianghui Ma , Lauren A. Simon , Kaitlyn E. Naughton , Rei Mizuno , Tatiana Karakasheva , Emily A. McMillan , Kelly A. Whelan , Donita C. Brady , Sydney M. Shaffer , Kathryn E. Hamilton","doi":"10.1016/j.jcmgh.2023.12.001","DOIUrl":null,"url":null,"abstract":"<div><h3>Background & Aims</h3><p>The intestinal epithelium interfaces with a diverse milieu of luminal contents while maintaining robust digestive and barrier functions. Facultative intestinal stem cells are cells that survive tissue injury and divide to re-establish the epithelium. Prior studies have shown autophagic state as functional marker of facultative intestinal stem cells, but regulatory mechanisms are not known. The current study evaluated a post-transcriptional regulation of autophagy as an important factor for facultative stem cell state and tissue regeneration.</p></div><div><h3>Methods</h3><p>We evaluated stem cell composition, autophagic vesicle content, organoid formation, and in vivo regeneration in mice with intestinal epithelial deletion of the RNA binding protein <em>IGF2</em> messenger RNA binding protein 1 (IMP1). The contribution of autophagy to resulting in vitro and in vivo phenotypes was evaluated via genetic inactivation of <em>Atg7</em>. Molecular analyses of IMP1 modulation of autophagy at the protein and transcript localization levels were performed using IMP1 mutant studies and single-molecule fluorescent in situ hybridization.</p></div><div><h3>Results</h3><p>Epithelial <em>Imp1</em> deletion reduced leucine rich repeat containing G protein coupled receptor 5 cell frequency but enhanced both organoid formation efficiency and in vivo regeneration after irradiation. We confirmed prior studies showing increased autophagy with IMP1 deletion. Deletion of <em>Atg7</em> reversed the enhanced regeneration observed with <em>Imp1</em> deletion. IMP1 deletion or mutation of IMP1 phosphorylation sites enhanced expression of essential autophagy protein microtubule-associated protein 1 light chain 3β. Furthermore, immunofluorescence imaging coupled with single-molecule fluorescent in situ hybridization showed IMP1 colocalization with <em>MAP1LC3B</em> transcripts at homeostasis. Stress induction led to decreased colocalization.</p></div><div><h3>Conclusions</h3><p>Depletion of IMP1 enhances autophagy, which promotes intestinal regeneration via expansion of facultative intestinal stem cells.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"17 3","pages":"Pages 439-451"},"PeriodicalIF":7.1000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X2300214X/pdfft?md5=a5294ecfdf885b7c2780c0ea378dd133&pid=1-s2.0-S2352345X2300214X-main.pdf","citationCount":"0","resultStr":"{\"title\":\"IGF2BP1/IMP1 Deletion Enhances a Facultative Stem Cell State via Regulation of MAP1LC3B\",\"authors\":\"Louis R. Parham , Patrick A. Williams , Kay Katada , Shaneice K. Nettleford , Priya Chatterji , Kofi K. Acheampong , Charles H. Danan , Xianghui Ma , Lauren A. Simon , Kaitlyn E. Naughton , Rei Mizuno , Tatiana Karakasheva , Emily A. McMillan , Kelly A. Whelan , Donita C. Brady , Sydney M. Shaffer , Kathryn E. Hamilton\",\"doi\":\"10.1016/j.jcmgh.2023.12.001\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background & Aims</h3><p>The intestinal epithelium interfaces with a diverse milieu of luminal contents while maintaining robust digestive and barrier functions. Facultative intestinal stem cells are cells that survive tissue injury and divide to re-establish the epithelium. Prior studies have shown autophagic state as functional marker of facultative intestinal stem cells, but regulatory mechanisms are not known. The current study evaluated a post-transcriptional regulation of autophagy as an important factor for facultative stem cell state and tissue regeneration.</p></div><div><h3>Methods</h3><p>We evaluated stem cell composition, autophagic vesicle content, organoid formation, and in vivo regeneration in mice with intestinal epithelial deletion of the RNA binding protein <em>IGF2</em> messenger RNA binding protein 1 (IMP1). The contribution of autophagy to resulting in vitro and in vivo phenotypes was evaluated via genetic inactivation of <em>Atg7</em>. Molecular analyses of IMP1 modulation of autophagy at the protein and transcript localization levels were performed using IMP1 mutant studies and single-molecule fluorescent in situ hybridization.</p></div><div><h3>Results</h3><p>Epithelial <em>Imp1</em> deletion reduced leucine rich repeat containing G protein coupled receptor 5 cell frequency but enhanced both organoid formation efficiency and in vivo regeneration after irradiation. We confirmed prior studies showing increased autophagy with IMP1 deletion. Deletion of <em>Atg7</em> reversed the enhanced regeneration observed with <em>Imp1</em> deletion. IMP1 deletion or mutation of IMP1 phosphorylation sites enhanced expression of essential autophagy protein microtubule-associated protein 1 light chain 3β. Furthermore, immunofluorescence imaging coupled with single-molecule fluorescent in situ hybridization showed IMP1 colocalization with <em>MAP1LC3B</em> transcripts at homeostasis. 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IGF2BP1/IMP1 Deletion Enhances a Facultative Stem Cell State via Regulation of MAP1LC3B
Background & Aims
The intestinal epithelium interfaces with a diverse milieu of luminal contents while maintaining robust digestive and barrier functions. Facultative intestinal stem cells are cells that survive tissue injury and divide to re-establish the epithelium. Prior studies have shown autophagic state as functional marker of facultative intestinal stem cells, but regulatory mechanisms are not known. The current study evaluated a post-transcriptional regulation of autophagy as an important factor for facultative stem cell state and tissue regeneration.
Methods
We evaluated stem cell composition, autophagic vesicle content, organoid formation, and in vivo regeneration in mice with intestinal epithelial deletion of the RNA binding protein IGF2 messenger RNA binding protein 1 (IMP1). The contribution of autophagy to resulting in vitro and in vivo phenotypes was evaluated via genetic inactivation of Atg7. Molecular analyses of IMP1 modulation of autophagy at the protein and transcript localization levels were performed using IMP1 mutant studies and single-molecule fluorescent in situ hybridization.
Results
Epithelial Imp1 deletion reduced leucine rich repeat containing G protein coupled receptor 5 cell frequency but enhanced both organoid formation efficiency and in vivo regeneration after irradiation. We confirmed prior studies showing increased autophagy with IMP1 deletion. Deletion of Atg7 reversed the enhanced regeneration observed with Imp1 deletion. IMP1 deletion or mutation of IMP1 phosphorylation sites enhanced expression of essential autophagy protein microtubule-associated protein 1 light chain 3β. Furthermore, immunofluorescence imaging coupled with single-molecule fluorescent in situ hybridization showed IMP1 colocalization with MAP1LC3B transcripts at homeostasis. Stress induction led to decreased colocalization.
Conclusions
Depletion of IMP1 enhances autophagy, which promotes intestinal regeneration via expansion of facultative intestinal stem cells.
期刊介绍：
"Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology.
CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.
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