{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T16:41:52Z","timestamp":1773333712777,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1013052","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T00:00:00Z","timestamp":1748822400000}}],"reference-count":19,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T00:00:00Z","timestamp":1747008000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["ALWOP.265"],"award-info":[{"award-number":["ALWOP.265"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["Vici 09150181910016"],"award-info":[{"award-number":["Vici 09150181910016"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Estimating production and loss rates of cell populations is essential but difficult. The current state-of-the-art method to estimate these rates involves mathematical modelling of deuterium labelling experiments. Current models typically assume that the labelling in the precursors of the population of interest (POI) is proportional to the deuterium enrichment in body water\/glucose. This assumption is not always true and it is known that this can have a significant effect on the rates estimated from labelling experiments. Here we quantify the effect that different turnover (replacement) rates of the precursors can have on the estimated proliferation and loss rates of a POI by explicitly modelling the dynamics of the precursors. We first confirm earlier results that the labelling curve of the POI only reflects its own turnover rate if either the turnover rate of the precursors is sufficiently fast, or the contribution from the precursors is sufficiently small. Next, we describe three realistic scenarios with a slowly turning over precursor population, and show how this changes the interpretation of the different parameter estimates. Our analyses underpin that uniquely identifying the turnover rate of a POI requires measurements (or knowledge) on the turnover of its immediate precursors.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1013052","type":"journal-article","created":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T18:07:01Z","timestamp":1747073221000},"page":"e1013052","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["How are estimated cellular turnover rates influenced by the dynamics of a source population?"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7816-1053","authenticated-orcid":true,"given":"Arpit C.","family":"Swain","sequence":"first","affiliation":[]},{"given":"Jos\u00e9 A. M.","family":"Borghans","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2130-691X","authenticated-orcid":true,"given":"Rob J.","family":"de Boer","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2025,5,12]]},"reference":[{"issue":"4571","key":"pcbi.1013052.ref001","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1126\/science.7123245","article-title":"Monoclonal antibody to 5-bromo- and 5-iododeoxyuridine: A new reagent for detection of DNA replication","volume":"218","author":"HG Gratzner","year":"1982","journal-title":"Science"},{"issue":"6","key":"pcbi.1013052.ref002","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1182\/blood.V24.6.780.780","article-title":"Analytical review: the kinetics of granulopoiesis in normal man","volume":"24","author":"GE Cartwright","year":"1964","journal-title":"Blood"},{"issue":"2","key":"pcbi.1013052.ref003","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1073\/pnas.95.2.708","article-title":"Measurement of cell proliferation by labeling of DNA with stable isotope-labeled glucose: studies in vitro, in animals, and in humans","volume":"95","author":"DC Macallan","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pcbi.1013052.ref004","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1111\/imr.12693","article-title":"Current best estimates for the average lifespans of mouse and human leukocytes: reviewing two decades of deuterium-labeling experiments","volume":"285","author":"JAM Borghans","year":"2018","journal-title":"Immunol Rev"},{"issue":"12","key":"pcbi.1013052.ref005","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/S1471-4906(02)02337-2","article-title":"Lymphocyte kinetics: the interpretation of labelling data","volume":"23","author":"B Asquith","year":"2002","journal-title":"Trends Immunol"},{"key":"pcbi.1013052.ref006","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.jtbi.2012.12.025","article-title":"Quantifying T lymphocyte turnover","volume":"327","author":"RJ De Boer","year":"2013","journal-title":"J Theor Biol"},{"issue":"10","key":"pcbi.1013052.ref007","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1004355","article-title":"Reconciling estimates of cell proliferation from stable isotope labeling experiments","volume":"11","author":"R Ahmed","year":"2015","journal-title":"PLoS Comput Biol"},{"issue":"9","key":"pcbi.1013052.ref008","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1038\/nprot.2009.117","article-title":"Measurement of proliferation and disappearance of rapid turnover cell populations in human studies using deuterium-labeled glucose","volume":"4","author":"DC Macallan","year":"2009","journal-title":"Nat Protoc"},{"issue":"26","key":"pcbi.1013052.ref009","doi-asserted-by":"crossref","first-page":"3431","DOI":"10.1182\/blood-2016-03-700336","article-title":"Human neutrophil kinetics: modeling of stable isotope labeling data supports short blood neutrophil half-lives","volume":"127","author":"J Lahoz-Beneytez","year":"2016","journal-title":"Blood"},{"key":"pcbi.1013052.ref010","article-title":"The impact of model assumptions in interpreting cell kinetics studies","author":"A Yan","year":"2025","journal-title":"PLOS Comput Biol"},{"issue":"2","key":"pcbi.1013052.ref011","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1000666","article-title":"Explicit kinetic heterogeneity: mathematical models for interpretation of deuterium labeling of heterogeneous cell populations","volume":"6","author":"VV Ganusov","year":"2010","journal-title":"PLoS Comput Biol"},{"issue":"13","key":"pcbi.1013052.ref012","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1182\/blood-2013-03-488411","article-title":"Closing the gap between T-cell life span estimates from stable isotope-labeling studies in mice and humans","volume":"122","author":"L Westera","year":"2013","journal-title":"Blood"},{"issue":"6","key":"pcbi.1013052.ref013","doi-asserted-by":"crossref","first-page":"3436","DOI":"10.4049\/jimmunol.1001421","article-title":"Homeostatic turnover of virus-specific memory CD8 T cells occurs stochastically and is independent of CD4 T cell help","volume":"185","author":"DK Choo","year":"2010","journal-title":"J Immunol"},{"issue":"16","key":"pcbi.1013052.ref014","doi-asserted-by":"crossref","first-page":"6115","DOI":"10.1073\/pnas.0709713105","article-title":"Sparse production but preferential incorporation of recently produced naive T cells in the human peripheral pool","volume":"105","author":"N Vrisekoop","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1013052.ref015","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2020.108501","article-title":"CD57+ Memory T Cells Proliferate In Vivo","volume":"33","author":"R Ahmed","year":"2020","journal-title":"Cell Rep"},{"issue":"5","key":"pcbi.1013052.ref016","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.coi.2013.09.003","article-title":"Lineage relationship of effector and memory T cells","volume":"25","author":"NP Restifo","year":"2013","journal-title":"Curr Opin Immunol"},{"key":"pcbi.1013052.ref017","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1146\/annurev.immunol.22.012703.104702","article-title":"Central memory and effector memory T cell subsets: function, generation, and maintenance","volume":"22","author":"F Sallusto","year":"2004","journal-title":"Annu Rev Immunol"},{"key":"pcbi.1013052.ref018","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.23013","article-title":"Memory CD4 T cell subsets are kinetically heterogeneous and replenished from naive T cells at high levels","volume":"6","author":"G Gossel","year":"2017","journal-title":"Elife"},{"issue":"9","key":"pcbi.1013052.ref019","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1084\/jem.194.9.1277","article-title":"Increased turnover of T lymphocytes in HIV-1 infection and its reduction by antiretroviral therapy","volume":"194","author":"H Mohri","year":"2001","journal-title":"J Exp Med"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1013052","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T00:00:00Z","timestamp":1748822400000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1013052","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T18:23:37Z","timestamp":1748888617000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1013052"}},"subtitle":[],"editor":[{"given":"Ruy M.","family":"Ribeiro","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2025,5,12]]},"references-count":19,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5,12]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1013052","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1013052","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,12]]}}}