{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:44:43Z","timestamp":1790750683190,"version":"4.1.0"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,9,24]],"date-time":"2019-09-24T00:00:00Z","timestamp":1569283200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,9,24]],"date-time":"2019-09-24T00:00:00Z","timestamp":1569283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"The King Gustav V Jubilee Clinic Cancer Foundation, Gothenburg, Sweden, The Swedish Cancer Society, Stockholm, Sweden, and The Swedish State under the ALF agreement, Sweden."},{"name":"Sahlgrenska Academy International Starting Grant, Gothenburg, Sweden"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chronic intestinal injury after pelvic radiotherapy affects countless cancer survivors worldwide. A comprehensive understanding of the long-term injury dynamics is prevented in available animal models. With linear accelerators that are used to treat cancer in patients, we irradiated a small volume encompassing the colorectum in mice with four fractions of 8\u2009Gy per fraction. We then determined the long-term dynamics of mucosal injury, repair, and the duration of inflammation. We show that crypt fission, not cell proliferation, is the main long-term mechanism for rescuing crypt density after irradiation, and provides a potentially wide window for clinical interventions. Persisting macrophage aggregations indicate a chronic mucosal inflammation. A better understanding as to how crypt fission is triggered and why it fails to repair fully the mucosa may help restore bowel health after pelvic radiotherapy. Moreover, anti-inflammatory interventions, even if implemented long after completed radiotherapy, could promote bowel health in pelvic cancer survivors.<\/jats:p>","DOI":"10.1038\/s41598-019-50023-4","type":"journal-article","created":{"date-parts":[[2019,9,24]],"date-time":"2019-09-24T10:02:51Z","timestamp":1569319371000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Long-term mucosal injury and repair in a murine model of pelvic radiotherapy"],"prefix":"10.1038","volume":"9","author":[{"given":"Dilip K.","family":"Malipatlolla","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piyush","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Sj\u00f6berg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sravani","family":"Devarakonda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Kalm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Angenete","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elinor Bexe","family":"Lindskog","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Grand\u00e9r","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Persson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Stringer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrica","family":"Wilder\u00e4ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Swanpalmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans Georg","family":"Kuhn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnar","family":"Steineck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Bull","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,9,24]]},"reference":[{"key":"50023_CR1","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1016\/S1470-2045(10)70026-7","volume":"11","author":"HJ Andreyev","year":"2010","unstructured":"Andreyev, H. J., Wotherspoon, A., Denham, J. W. & Hauer-Jensen, M. Defining pelvic-radiation disease for the survivorship era. Lancet Oncol 11, 310\u2013312, https:\/\/doi.org\/10.1016\/S1470-2045(10)70026-7 (2010).","journal-title":"Lancet Oncol"},{"key":"50023_CR2","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1111\/IGC.0b013e3181d373bf","volume":"20","author":"G Dunberger","year":"2010","unstructured":"Dunberger, G. et al. Fecal incontinence affecting quality of life and social functioning among long-term gynecological cancer survivors. Int J Gynecol Cancer 20, 449\u2013460, https:\/\/doi.org\/10.1111\/IGC.0b013e3181d373bf (2010).","journal-title":"Int J Gynecol Cancer"},{"key":"50023_CR3","doi-asserted-by":"publisher","first-page":"e0171461","DOI":"10.1371\/journal.pone.0171461","volume":"12","author":"G Steineck","year":"2017","unstructured":"Steineck, G. et al. Identifying radiation-induced survivorship syndromes affecting bowel health in a cohort of gynecological cancer survivors. PLoS One 12, e0171461, https:\/\/doi.org\/10.1371\/journal.pone.0171461 (2017).","journal-title":"PLoS One"},{"key":"50023_CR4","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1038\/bjc.1998.618","volume":"78","author":"CS Potten","year":"1998","unstructured":"Potten, C. S. & Grant, H. K. The relationship between ionizing radiation-induced apoptosis and stem cells in the small and large intestine. Br J Cancer 78, 993\u20131003 (1998).","journal-title":"Br J Cancer"},{"key":"50023_CR5","doi-asserted-by":"publisher","first-page":"2194","DOI":"10.1007\/s10350-007-9065-7","volume":"50","author":"A Mihaescu","year":"2007","unstructured":"Mihaescu, A. et al. Critical role of P-selectin and lymphocyte function antigen-1 in radiation-induced leukocyte-endothelial cell interactions in the colon. Dis Colon Rectum 50, 2194\u20132202, https:\/\/doi.org\/10.1007\/s10350-007-9065-7 (2007).","journal-title":"Dis Colon Rectum"},{"key":"50023_CR6","doi-asserted-by":"publisher","first-page":"279","DOI":"10.4240\/wjgs.v7.i11.279","volume":"7","author":"KA Morris","year":"2015","unstructured":"Morris, K. A. & Haboubi, N. Y. Pelvic radiation therapy: Between delight and disaster. World J Gastrointest Surg 7, 279\u2013288, https:\/\/doi.org\/10.4240\/wjgs.v7.i11.279 (2015).","journal-title":"World J Gastrointest Surg"},{"key":"50023_CR7","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1126\/science.1060191","volume":"293","author":"F Paris","year":"2001","unstructured":"Paris, F. et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 293, 293\u2013297, https:\/\/doi.org\/10.1126\/science.1060191 (2001).","journal-title":"Science"},{"key":"50023_CR8","first-page":"1","volume":"398","author":"PBDT Andreo","year":"2000","unstructured":"Andreo, P. B. D. T. et al. Absorbed dose determination in external beam radiotherapy: an International Code of Practice for dosimetry based on standards of absorbed dose to water. IAEA Technical Reports Series no. 398, 1\u2013183 (2000).","journal-title":"IAEA Technical Reports Series no."},{"key":"50023_CR9","doi-asserted-by":"publisher","first-page":"02017","DOI":"10.1152\/ajpgi.00113.2017","volume":"00113","author":"CM Bull","year":"2017","unstructured":"Bull, C. M. et al. A novel mouse model of radiation-induced cancer survivorship diseases of the gut. Am J Physiol Gastrointest Liver Physiol, ajpgi 00113, 02017, https:\/\/doi.org\/10.1152\/ajpgi.00113.2017 (2017).","journal-title":"Am J Physiol Gastrointest Liver Physiol, ajpgi"},{"key":"50023_CR10","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1038\/nrc1950","volume":"6","author":"SM Bentzen","year":"2006","unstructured":"Bentzen, S. M. Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology. Nat Rev Cancer 6, 702\u2013713, https:\/\/doi.org\/10.1038\/nrc1950 (2006).","journal-title":"Nat Rev Cancer"},{"key":"50023_CR11","doi-asserted-by":"publisher","first-page":"13879","DOI":"10.1073\/pnas.94.25.13879","volume":"94","author":"ZW Chen","year":"1997","unstructured":"Chen, Z. W. et al. Identification, isolation, and characterization of daintain (allograft inflammatory factor 1), a macrophage polypeptide with effects on insulin secretion and abundantly present in the pancreas of prediabetic BB rats. Proc Natl Acad Sci USA 94, 13879\u201313884 (1997).","journal-title":"Proc Natl Acad Sci USA"},{"key":"50023_CR12","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1007\/s00441-007-0474-7","volume":"330","author":"C Kohler","year":"2007","unstructured":"Kohler, C. Allograft inflammatory factor-1\/Ionized calcium-binding adapter molecule 1 is specifically expressed by most subpopulations of macrophages and spermatids in testis. Cell Tissue Res 330, 291\u2013302, https:\/\/doi.org\/10.1007\/s00441-007-0474-7 (2007).","journal-title":"Cell Tissue Res"},{"key":"50023_CR13","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1002\/ar.1092100311","volume":"210","author":"DA Hume","year":"1984","unstructured":"Hume, D. A., Perry, V. H. & Gordon, S. The mononuclear phagocyte system of the mouse defined by immunohistochemical localisation of antigen F4\/80: macrophages associated with epithelia. Anat Rec 210, 503\u2013512, https:\/\/doi.org\/10.1002\/ar.1092100311 (1984).","journal-title":"Anat Rec"},{"key":"50023_CR14","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1080\/09553000802078388","volume":"84","author":"SM Moyes","year":"2008","unstructured":"Moyes, S. M. et al. Changes produced by external radiation in parameters influencing intestinal permeability and microparticle uptake in vitro. Int J Radiat Biol 84, 467\u2013486, https:\/\/doi.org\/10.1080\/09553000802078388 (2008).","journal-title":"Int J Radiat Biol"},{"key":"50023_CR15","doi-asserted-by":"publisher","first-page":"e27127","DOI":"10.4161\/onci.27127","volume":"2","author":"DH Madsen","year":"2013","unstructured":"Madsen, D. H. & Bugge, T. H. Imaging collagen degradation in vivo highlights a key role for M2-polarized macrophages in extracellular matrix degradation. Oncoimmunology 2, e27127, https:\/\/doi.org\/10.4161\/onci.27127 (2013).","journal-title":"Oncoimmunology"},{"key":"50023_CR16","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/S0006-3495(87)83215-0","volume":"52","author":"J Totafurno","year":"1987","unstructured":"Totafurno, J., Bjerknes, M. & Cheng, H. The crypt cycle. Crypt and villus production in the adult intestinal epithelium. Biophys J 52, 279\u2013294, https:\/\/doi.org\/10.1016\/S0006-3495(87)83215-0 (1987).","journal-title":"Biophys J"},{"key":"50023_CR17","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.1172\/JCI10229","volume":"105","author":"C Booth","year":"2000","unstructured":"Booth, C. & Potten, C. S. Gut instincts: thoughts on intestinal epithelial stem cells. J Clin Invest 105, 1493\u20131499, https:\/\/doi.org\/10.1172\/JCI10229 (2000).","journal-title":"J Clin Invest"},{"key":"50023_CR18","first-page":"843","volume":"151","author":"HS Park","year":"1997","unstructured":"Park, H. S. et al. Effects of epidermal growth factor and dimethylhydrazine on crypt size, cell proliferation, and crypt fission in the rat colon. Cell proliferation and crypt fission are controlled independently. Am J Pathol 151, 843\u2013852 (1997).","journal-title":"Am J Pathol"},{"key":"50023_CR19","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s13287-017-0763-3","volume":"9","author":"P Bhanja","year":"2018","unstructured":"Bhanja, P., Norris, A., Gupta-Saraf, P., Hoover, A. & Saha, S. BCN057 induces intestinal stem cell repair and mitigates radiation-induced intestinal injury. Stem Cell Res Ther 9, 26, https:\/\/doi.org\/10.1186\/s13287-017-0763-3 (2018).","journal-title":"Stem Cell Res Ther"},{"key":"50023_CR20","doi-asserted-by":"publisher","first-page":"510","DOI":"10.2307\/3572263","volume":"32","author":"S Lesher","year":"1967","unstructured":"Lesher, S. Compensatory reactions in intestinal crypt cells after 300 Roentgens of cobalt-60 gamma irradiation. Radiat Res 32, 510\u2013519 (1967).","journal-title":"Radiat Res"},{"key":"50023_CR21","doi-asserted-by":"publisher","first-page":"G377","DOI":"10.1152\/ajpgi.00034.2012","volume":"303","author":"TE Riehl","year":"2012","unstructured":"Riehl, T. E., Ee, X. & Stenson, W. F. Hyaluronic acid regulates normal intestinal and colonic growth in mice. Am J Physiol Gastrointest Liver Physiol 303, G377\u2013388, https:\/\/doi.org\/10.1152\/ajpgi.00034.2012 (2012).","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"50023_CR22","doi-asserted-by":"publisher","first-page":"1348","DOI":"10.1016\/S0016-5085(03)00288-9","volume":"124","author":"PD Ottewell","year":"2003","unstructured":"Ottewell, P. D. et al. Progastrin stimulates murine colonic epithelial mitosis after DNA damage. Gastroenterology 124, 1348\u20131357 (2003).","journal-title":"Gastroenterology"},{"key":"50023_CR23","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1016\/j.cell.2006.04.030","volume":"125","author":"J Holmberg","year":"2006","unstructured":"Holmberg, J. et al. EphB receptors coordinate migration and proliferation in the intestinal stem cell niche. Cell 125, 1151\u20131163, https:\/\/doi.org\/10.1016\/j.cell.2006.04.030 (2006).","journal-title":"Cell"},{"key":"50023_CR24","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1111\/j.0959-9673.2005.00422.x","volume":"86","author":"N Mandir","year":"2005","unstructured":"Mandir, N., FitzGerald, A. J. & Goodlad, R. A. Differences in the effects of age on intestinal proliferation, crypt fission and apoptosis on the small intestine and the colon of the rat. Int J Exp Pathol 86, 125\u2013130, https:\/\/doi.org\/10.1111\/j.0959-9673.2005.00422.x (2005).","journal-title":"Int J Exp Pathol"},{"key":"50023_CR25","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1136\/gut.2004.056010","volume":"54","author":"RK Wali","year":"2005","unstructured":"Wali, R. K. et al. Increased microvascular blood content is an early event in colon carcinogenesis. Gut 54, 654\u2013660, https:\/\/doi.org\/10.1136\/gut.2004.056010 (2005).","journal-title":"Gut"},{"key":"50023_CR26","doi-asserted-by":"publisher","unstructured":"Steineck, G. et al. Radiation physiology - evidence for a higher biological effect of 24 Gy in four fractions as compared to three. Acta Oncol, 1\u20133, https:\/\/doi.org\/10.1080\/0284186X.2017.1309062 (2017).","DOI":"10.1080\/0284186X.2017.1309062"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50023-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50023-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50023-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T13:54:31Z","timestamp":1671285271000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50023-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,24]]},"references-count":26,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["50023"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-50023-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,24]]},"assertion":[{"value":"11 January 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 September 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 September 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"13803"}}