Extrusion of BMP2+ surface colonocytes promotes stromal remodeling and tissue regeneration
Abstract The colon epithelium frequently incurs damage through toxic influences. Repair is rapid, mediated by cellular plasticity and acquisition of the highly proliferative regenerative state. However, the mechanisms that promote the regenerative state are not well understood. Here, we reveal that...
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| Format: | Article |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59474-y |
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| author | Julian Heuberger Lichao Liu Hilmar Berger Joop van den Heuvel Manqiang Lin Stefanie Müllerke Safak Bayram Giulia Beccaceci Hugo de Jonge Ermanno Gherardi Michael Sigal |
| author_facet | Julian Heuberger Lichao Liu Hilmar Berger Joop van den Heuvel Manqiang Lin Stefanie Müllerke Safak Bayram Giulia Beccaceci Hugo de Jonge Ermanno Gherardi Michael Sigal |
| author_sort | Julian Heuberger |
| collection | DOAJ |
| description | Abstract The colon epithelium frequently incurs damage through toxic influences. Repair is rapid, mediated by cellular plasticity and acquisition of the highly proliferative regenerative state. However, the mechanisms that promote the regenerative state are not well understood. Here, we reveal that upon injury and subsequent inflammatory response, IFN-γ drives widespread epithelial remodeling. IFN-γ promotes rapid apoptotic extrusion of fully differentiated surface colonocytes, while simultaneously causing differentiation of crypt-base stem and progenitor cells towards a colonocyte-like lineage. However, unlike homeostatic colonocytes, these IFN-γ-induced colonocytes neither respond to nor produce BMP-2 but retain regenerative capacity. The reduction of BMP-2-producing epithelial surface cells causes a remodeling of the surrounding mesenchymal niche, inducing high expression of HGF, which promotes proliferation of the IFN-γ-induced colonocytes. This mechanism of lineage replacement and subsequent remodeling of the mesenchymal niche enables tissue-wide adaptation to injury and efficient repair. |
| format | Article |
| id | doaj-art-5f9bd44e54e84974a8181beee698f992 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-5f9bd44e54e84974a8181beee698f9922025-08-20T02:10:49ZengNature PortfolioNature Communications2041-17232025-05-0116111710.1038/s41467-025-59474-yExtrusion of BMP2+ surface colonocytes promotes stromal remodeling and tissue regenerationJulian Heuberger0Lichao Liu1Hilmar Berger2Joop van den Heuvel3Manqiang Lin4Stefanie Müllerke5Safak Bayram6Giulia Beccaceci7Hugo de Jonge8Ermanno Gherardi9Michael Sigal10Department of Hepatology and Gastroenterology, Charité—Universitätsmedizin BerlinDepartment of Hepatology and Gastroenterology, Charité—Universitätsmedizin BerlinDepartment of Hepatology and Gastroenterology, Charité—Universitätsmedizin BerlinHelmholtz-Zentrum für Infektionsforschung GmbHDepartment of Hepatology and Gastroenterology, Charité—Universitätsmedizin BerlinDepartment of Hepatology and Gastroenterology, Charité—Universitätsmedizin BerlinDepartment of Hepatology and Gastroenterology, Charité—Universitätsmedizin BerlinDepartment of Hepatology and Gastroenterology, Charité—Universitätsmedizin BerlinImmunology and General Pathology Unit, Department of Molecular Medicine, Università di PaviaImmunology and General Pathology Unit, Department of Molecular Medicine, Università di PaviaDepartment of Hepatology and Gastroenterology, Charité—Universitätsmedizin BerlinAbstract The colon epithelium frequently incurs damage through toxic influences. Repair is rapid, mediated by cellular plasticity and acquisition of the highly proliferative regenerative state. However, the mechanisms that promote the regenerative state are not well understood. Here, we reveal that upon injury and subsequent inflammatory response, IFN-γ drives widespread epithelial remodeling. IFN-γ promotes rapid apoptotic extrusion of fully differentiated surface colonocytes, while simultaneously causing differentiation of crypt-base stem and progenitor cells towards a colonocyte-like lineage. However, unlike homeostatic colonocytes, these IFN-γ-induced colonocytes neither respond to nor produce BMP-2 but retain regenerative capacity. The reduction of BMP-2-producing epithelial surface cells causes a remodeling of the surrounding mesenchymal niche, inducing high expression of HGF, which promotes proliferation of the IFN-γ-induced colonocytes. This mechanism of lineage replacement and subsequent remodeling of the mesenchymal niche enables tissue-wide adaptation to injury and efficient repair.https://doi.org/10.1038/s41467-025-59474-y |
| spellingShingle | Julian Heuberger Lichao Liu Hilmar Berger Joop van den Heuvel Manqiang Lin Stefanie Müllerke Safak Bayram Giulia Beccaceci Hugo de Jonge Ermanno Gherardi Michael Sigal Extrusion of BMP2+ surface colonocytes promotes stromal remodeling and tissue regeneration Nature Communications |
| title | Extrusion of BMP2+ surface colonocytes promotes stromal remodeling and tissue regeneration |
| title_full | Extrusion of BMP2+ surface colonocytes promotes stromal remodeling and tissue regeneration |
| title_fullStr | Extrusion of BMP2+ surface colonocytes promotes stromal remodeling and tissue regeneration |
| title_full_unstemmed | Extrusion of BMP2+ surface colonocytes promotes stromal remodeling and tissue regeneration |
| title_short | Extrusion of BMP2+ surface colonocytes promotes stromal remodeling and tissue regeneration |
| title_sort | extrusion of bmp2 surface colonocytes promotes stromal remodeling and tissue regeneration |
| url | https://doi.org/10.1038/s41467-025-59474-y |
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