{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:17:25Z","timestamp":1792804645286,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1009516","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T00:00:00Z","timestamp":1636588800000}}],"reference-count":110,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL154150"],"award-info":[{"award-number":["R01HL154150"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL154150"],"award-info":[{"award-number":["R01HL154150"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL154150"],"award-info":[{"award-number":["R01HL154150"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL154150"],"award-info":[{"award-number":["R01HL154150"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>The spleen, the largest secondary lymphoid organ in humans, not only fulfils a broad range of immune functions, but also plays an important role in red blood cell\u2019s (RBC) life cycle. Although much progress has been made to elucidate the critical biological processes involved in the maturation of young RBCs (reticulocytes) as well as removal of senescent RBCs in the spleen, the underlying mechanisms driving these processes are still obscure. Herein, we perform a computational study to simulate the passage of RBCs through interendothelial slits (IES) in the spleen at different stages of their lifespan and investigate the role of the spleen in facilitating the maturation of reticulocytes and in clearing the senescent RBCs. Our simulations reveal that at the beginning of the RBC life cycle, intracellular non-deformable particles in reticulocytes can be biomechanically expelled from the cell upon passage through IES, an insightful explanation of why this peculiar \u201cpitting\u201d process is spleen-specific. Our results also show that immature RBCs shed surface area by releasing vesicles after crossing IES and progressively acquire the biconcave shape of mature RBCs. These findings likely explain why RBCs from splenectomized patients are significantly larger than those from nonsplenectomized subjects. Finally, we show that at the end of their life span, senescent RBCs are not only retained by IES due to reduced deformability but also become susceptible to mechanical lysis under shear stress. This finding supports the recent hypothesis that transformation into a hemolyzed ghost is a prerequisite for phagocytosis of senescent RBCs. Altogether, our computational investigation illustrates critical biological processes in the spleen that cannot be observed <jats:italic>in vivo<\/jats:italic> or <jats:italic>in vitro<\/jats:italic> and offer insights into the role of the spleen in the RBC physiology.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009516","type":"journal-article","created":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T17:34:38Z","timestamp":1635788078000},"page":"e1009516","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":44,"title":["How the spleen reshapes and retains young and old red blood cells: A computational investigation"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1735-8899","authenticated-orcid":true,"given":"He","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7487-450X","authenticated-orcid":true,"given":"Zixiang Leonardo","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5476-5768","authenticated-orcid":true,"given":"Lu","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Buffet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9713-7120","authenticated-orcid":true,"given":"George Em","family":"Karniadakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,11,1]]},"reference":[{"issue":"8","key":"pcbi.1009516.ref001","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1038\/nri1669","article-title":"Structure and function of the spleen","volume":"5","author":"RE Mebius","year":"2005","journal-title":"Nature Reviews Immunology"},{"issue":"5","key":"pcbi.1009516.ref002","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1080\/01926230600867743","article-title":"Normal structure, function, and histology of the spleen","volume":"34","author":"MF Cesta","year":"2006","journal-title":"Toxicologic Pathology"},{"issue":"2","key":"pcbi.1009516.ref003","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.ijsu.2013.11.017","article-title":"Benefits and risks of splenectomy","volume":"12","author":"EP Weledji","year":"2014","journal-title":"International Journal of Surgery"},{"key":"pcbi.1009516.ref004","doi-asserted-by":"crossref","first-page":"7804","DOI":"10.1073\/pnas.1606751113","article-title":"Biomechanics of red blood cells in human spleen and consequences for physiology and disease","volume":"113","author":"IV Pivkin","year":"2016","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"2","key":"pcbi.1009516.ref005","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1182\/blood-2010-04-202911","article-title":"The pathogenesis of Plasmodium falciparum malaria in humans: insights from splenic physiology","volume":"117","author":"P Buffet","year":"2011","journal-title":"Blood"},{"issue":"3","key":"pcbi.1009516.ref006","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/0026-2862(87)90061-6","article-title":"Microcirculation of the spleen: new concepts, new challenges","volume":"34","author":"AC Groom","year":"1987","journal-title":"Microvascular Research"},{"key":"pcbi.1009516.ref007","doi-asserted-by":"crossref","first-page":"9","DOI":"10.3389\/fphys.2014.00009","article-title":"Of macrophages and red blood cells; 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