{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T07:11:19Z","timestamp":1781939479260,"version":"3.54.5"},"reference-count":62,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health","doi-asserted-by":"publisher","award":["1R01AI185510"],"award-info":[{"award-number":["1R01AI185510"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UF College of Medicine start-up package funds"},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["272983813 (TRR 179)"],"award-info":[{"award-number":["272983813 (TRR 179)"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["240245660 (SFB 1129)"],"award-info":[{"award-number":["240245660 (SFB 1129)"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The intestinal epithelium maintains tissue homeostasis through a dynamic balance of stem cell proliferation and differentiation. This process is spatially regulated along the crypt\u2013villus axis, with intestinal stem cells in the crypt regions proliferating and progenitor cells differentiating as they migrate toward the villus tips. Because the lumen of the gut contains very low levels of oxygen (i.e., hypoxia), an oxygen gradient is established within the crypt\u2013villus axis, placing the crypt regions under normoxic conditions while the villus tips reside under hypoxic conditions. Hence, intestinal epithelial cells encounter distinct oxygen microenvironments throughout their life span as they migrate along the crypt\u2013villus structures during their proliferation and differentiation process. To investigate how oxygen availability influences intestinal stem cell proliferation and differentiation, we cultured patient-derived human ileum organoids (i.e., enteroids) under normoxic (20% oxygen) or hypoxic (1% oxygen) conditions. Under hypoxia, enteroid growth was reduced, and expression of several stem cell markers, such as OLFM4 and LGR5, was decreased. Bulk and single-cell RNA sequencing revealed that hypoxia suppressed Wnt signaling pathways and reduced stem cell activity. Importantly, pharmacological stabilization of HIF-1\u03b1 under normoxic conditions recapitulated the hypoxia-induced loss of stemness, demonstrating that HIF-1\u03b1 is a key mediator of oxygen-dependent stem cell regulation in enteroids. These findings establish that physiological hypoxia in the intestinal epithelium directly regulates stem cell fate through HIF-1\u03b1 stabilization, providing mechanistic insight into how oxygen availability along the crypt\u2013villus structures controls intestinal homeostasis.<\/jats:p>","DOI":"10.3390\/cells15010031","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T14:27:47Z","timestamp":1766500067000},"page":"31","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hypoxia Affects Stem Cell Fate in Patient-Derived Ileum Enteroids in a HIF-1\u03b1-Dependent Manner"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9770-9873","authenticated-orcid":false,"given":"Zina M.","family":"Uckeley","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, 1200 Newell Drive, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmon","family":"Kee","sequence":"additional","affiliation":[{"name":"Virology, Department of Infectious Disease, University Hospital Heidelberg, Im Neuenheimer Feld 344, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy and Molecular Biotechnology (IPMB), BioQuant-Center for Quantitative Biology, Heidelberg University, 60120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Karaluz","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, 1200 Newell Drive, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashwini K.","family":"Sharma","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy and Molecular Biotechnology (IPMB), BioQuant-Center for Quantitative Biology, Heidelberg University, 60120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4436-8516","authenticated-orcid":false,"given":"Josmar","family":"Polanco","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, 1200 Newell Drive, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Freddie D.","family":"Ortiz Martinez","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, 1200 Newell Drive, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher I.","family":"Mederos","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, 1200 Newell Drive, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7868-0793","authenticated-orcid":false,"given":"Sorin O.","family":"Jacobs","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, 1200 Newell Drive, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid J.","family":"Groose","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, 1200 Newell Drive, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Ramsden","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, 1200 Newell Drive, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4989-4722","authenticated-orcid":false,"given":"Carl","family":"Herrmann","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy and Molecular Biotechnology (IPMB), BioQuant-Center for Quantitative Biology, Heidelberg University, 60120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan L.","family":"Stanifer","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, 1200 Newell Drive, Gainesville, FL 32610, USA"},{"name":"Molecular Virology, Department of Infectious Disease, University Hospital Heidelberg, Im Neuenheimer Feld 344, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steeve","family":"Boulant","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, 1200 Newell Drive, Gainesville, FL 32610, USA"},{"name":"Virology, Department of Infectious Disease, University Hospital Heidelberg, Im Neuenheimer Feld 344, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/nrg1840","article-title":"Organizing Cell Renewal in the Intestine: Stem Cells, Signals and Combinatorial Control","volume":"7","author":"Crosnier","year":"2006","journal-title":"Nat. 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