{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:17:26Z","timestamp":1772173046748,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010039","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T00:00:00Z","timestamp":1652832000000}}],"reference-count":36,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T00:00:00Z","timestamp":1651795200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DMS-1815406"],"award-info":[{"award-number":["DMS-1815406"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NIH\/NCI U54-CA217378"],"award-info":[{"award-number":["NIH\/NCI U54-CA217378"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DMS-1763272"],"award-info":[{"award-number":["DMS-1763272"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Feedback mechanisms within cell lineages are thought to be important for maintaining tissue homeostasis. Mathematical models that assume well-mixed cell populations, together with experimental data, have suggested that negative feedback from differentiated cells on the stem cell self-renewal probability can maintain a stable equilibrium and hence homeostasis. Cell lineage dynamics, however, are characterized by spatial structure, which can lead to different properties. Here, we investigate these dynamics using spatially explicit computational models, including cell division, differentiation, death, and migration \/ diffusion processes. According to these models, the negative feedback loop on stem cell self-renewal fails to maintain homeostasis, both under the assumption of strong spatial restrictions and fast migration \/ diffusion. Although homeostasis cannot be maintained, this feedback can regulate cell density and promote the formation of spatial structures in the model. Tissue homeostasis, however, can be achieved if spatially restricted negative feedback on self-renewal is combined with an experimentally documented spatial feedforward loop, in which stem cells regulate the fate of transit amplifying cells. This indicates that the dynamics of feedback regulation in tissue cell lineages are more complex than previously thought, and that combinations of spatially explicit control mechanisms are likely instrumental.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010039","type":"journal-article","created":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T13:59:59Z","timestamp":1651845599000},"page":"e1010039","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Spatial dynamics of feedback and feedforward regulation in cell lineages"],"prefix":"10.1371","volume":"18","author":[{"given":"Peter","family":"Uhl","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1759-0900","authenticated-orcid":true,"given":"John","family":"Lowengrub","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Komarova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8017-3707","authenticated-orcid":true,"given":"Dominik","family":"Wodarz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,5,6]]},"reference":[{"issue":"4","key":"pcbi.1010039.ref001","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.stem.2012.09.003","article-title":"Asymmetric stem cell division: precision for robustness","volume":"11","author":"M Inaba","year":"2012","journal-title":"Cell stem cell"},{"issue":"6","key":"pcbi.1010039.ref002","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.cell.2011.05.033","article-title":"Strategies for homeostatic stem cell self-renewal in adult tissues","volume":"145","author":"BD Simons","year":"2011","journal-title":"Cell"},{"issue":"1","key":"pcbi.1010039.ref003","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.cell.2010.09.016","article-title":"Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells","volume":"143","author":"HJ Snippert","year":"2010","journal-title":"Cell"},{"issue":"3","key":"pcbi.1010039.ref004","doi-asserted-by":"crossref","first-page":"e28","DOI":"10.1371\/journal.pcbi.0030028","article-title":"The stem cell population of the human colon crypt: analysis via methylation patterns.","volume":"3","author":"P Nicolas","year":"2007","journal-title":"PLoS computational biology"},{"issue":"1","key":"pcbi.1010039.ref005","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.ccr.2007.12.005","article-title":"Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells","volume":"13","author":"J Lee","year":"2008","journal-title":"Cancer cell"},{"issue":"47","key":"pcbi.1010039.ref006","doi-asserted-by":"crossref","first-page":"18983","DOI":"10.1073\/pnas.1107621108","article-title":"Evolutionary dynamics of feedback escape and the development of stem-cell-driven cancers","volume":"108","author":"IA Rodriguez-Brenes","year":"2011","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"19","key":"pcbi.1010039.ref007","doi-asserted-by":"crossref","first-page":"4131","DOI":"10.1242\/dev.065870","article-title":"Activin and GDF11 collaborate in feedback control of neuroepithelial stem cell proliferation and fate","volume":"138","author":"KK Gokoffski","year":"2011","journal-title":"Development"},{"issue":"1","key":"pcbi.1010039.ref008","doi-asserted-by":"crossref","first-page":"e15","DOI":"10.1371\/journal.pbio.1000015","article-title":"Cell lineages and the logic of proliferative control","volume":"7","author":"AD Lander","year":"2009","journal-title":"PLoS biology"},{"key":"pcbi.1010039.ref009","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.pharmthera.2014.11.001","article-title":"Targeting the TGFbeta pathway for cancer therapy","volume":"147","author":"C Neuzillet","year":"2015","journal-title":"Pharmacology & therapeutics"},{"issue":"3","key":"pcbi.1010039.ref010","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1007\/s10555-006-9006-2","article-title":"Transforming growth factor-beta in cancer and metastasis","volume":"25","author":"SB Jakowlew","year":"2006","journal-title":"Cancer metastasis reviews"},{"issue":"6","key":"pcbi.1010039.ref011","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/j.cellsig.2010.10.015","article-title":"Transforming growth factor-beta and the hallmarks of cancer","volume":"23","author":"M Tian","year":"2011","journal-title":"Cellular signalling"},{"issue":"3\u20134","key":"pcbi.1010039.ref012","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1007\/s10555-012-9375-7","article-title":"TGF-beta signalling and its role in cancer progression and metastasis","volume":"31","author":"Y Drabsch","year":"2012","journal-title":"Cancer metastasis reviews"},{"issue":"3","key":"pcbi.1010039.ref013","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/S0896-6273(00)00148-3","article-title":"Noggin antagonizes BMP signaling to create a niche for adult neurogenesis","volume":"28","author":"DA Lim","year":"2000","journal-title":"Neuron"},{"issue":"3","key":"pcbi.1010039.ref014","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.cellsig.2013.11.032","article-title":"Wnt signaling in adult intestinal stem cells and cancer","volume":"26","author":"M Krausova","year":"2014","journal-title":"Cellular signalling"},{"issue":"3","key":"pcbi.1010039.ref015","doi-asserted-by":"crossref","first-page":"e1004814","DOI":"10.1371\/journal.pcbi.1004814","article-title":"Feedback, Lineages and Self-Organizing Morphogenesis.","volume":"12","author":"S Kunche","year":"2016","journal-title":"PLoS computational biology"},{"key":"pcbi.1010039.ref016","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.jtbi.2012.02.030","article-title":"Multispecies model of cell lineages and feedback control in solid tumors","volume":"304","author":"H Youssefpour","year":"2012","journal-title":"Journal of theoretical biology"},{"issue":"9","key":"pcbi.1010039.ref017","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1158\/0008-5472.CAN-16-2434","article-title":"Cellular Hierarchy as a Determinant of Tumor Sensitivity to Chemotherapy","volume":"77","author":"IA Rodriguez-Brenes","year":"2017","journal-title":"Cancer research"},{"issue":"1","key":"pcbi.1010039.ref018","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1038\/s41598-018-21115-4","article-title":"Mathematical modeling of the impact of cytokine response of acute myeloid leukemia cells on patient prognosis","volume":"8","author":"T Stiehl","year":"2018","journal-title":"Sci Rep"},{"key":"pcbi.1010039.ref019","first-page":"1269","volume":"7","author":"O Arino","year":"1986","journal-title":"STABILITY ANALYSIS OF MODELS OF CELL PRODUCTION SYSTEMS Mathematical Modeling"},{"issue":"3","key":"pcbi.1010039.ref020","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1089\/scd.2008.0143","article-title":"Modeling of asymmetric cell division in hematopoietic stem cells\u2014regulation of self-renewal is essential for efficient repopulation","volume":"18","author":"A Marciniak-Czochra","year":"2009","journal-title":"Stem Cells Dev"},{"issue":"9","key":"pcbi.1010039.ref021","doi-asserted-by":"crossref","first-page":"e72847","DOI":"10.1371\/journal.pone.0072847","article-title":"Principles of regulation of self-renewing cell lineages","volume":"8","author":"NL Komarova","year":"2013","journal-title":"PloS one"},{"key":"pcbi.1010039.ref022","article-title":"Stability of Control Networks in Autonomous Homeostatic Regulation of Stem Cell Lineages.","author":"NL Komarova","year":"2017","journal-title":"Bulletin of mathematical biology"},{"key":"pcbi.1010039.ref023","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.jtbi.2017.06.033","article-title":"Determining the control networks regulating stem cell lineages in colonic crypts","volume":"429","author":"J Yang","year":"2017","journal-title":"Journal of theoretical biology"},{"issue":"1","key":"pcbi.1010039.ref024","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3934\/mbe.2009.6.59","article-title":"Feedback regulation in multistage cell lineages","volume":"6","author":"WC Lo","year":"2009","journal-title":"Math Biosci Eng"},{"issue":"sup1","key":"pcbi.1010039.ref025","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1080\/17513758.2011.558214","article-title":"Stability analysis of multi-compartment models for cell production systems","volume":"6","author":"Y Nakata","year":"2012","journal-title":"Journal of biological dynamics"},{"key":"pcbi.1010039.ref026","article-title":"Characterization of stem cells using mathematical models of multistage cell lineages","author":"T Stiehl","year":"2011","journal-title":"Mathematical and Computer Modelling"},{"issue":"4","key":"pcbi.1010039.ref027","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1007\/s11538-016-0161-5","article-title":"Feedback Regulation in a Cancer Stem Cell Model can Cause an Allee Effect.","volume":"78","author":"A Konstorum","year":"2016","journal-title":"Bulletin of mathematical biology"},{"issue":"10","key":"pcbi.1010039.ref028","doi-asserted-by":"crossref","first-page":"3145","DOI":"10.1016\/j.bpj.2010.09.034","article-title":"Spatial dynamics of multistage cell lineages in tissue stratification","volume":"99","author":"C-S Chou","year":"2010","journal-title":"Biophysical journal"},{"issue":"Pt A","key":"pcbi.1010039.ref029","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.mbs.2015.08.009","article-title":"Characterizing inhibited tumor growth in stem-cell-driven non-spatial cancers","volume":"270","author":"IA Rodriguez-Brenes","year":"2015","journal-title":"Mathematical biosciences"},{"key":"pcbi.1010039.ref030","doi-asserted-by":"crossref","first-page":"110499","DOI":"10.1016\/j.jtbi.2020.110499","article-title":"Effect of feedback regulation on stem cell fractions in tissues and tumors: Understanding chemoresistance in cancer","volume":"509","author":"LD Weiss","year":"2021","journal-title":"Journal of theoretical biology"},{"issue":"19","key":"pcbi.1010039.ref031","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1016\/j.yexcr.2011.07.010","article-title":"Stem cell self-renewal in intestinal crypt","volume":"317","author":"BD Simons","year":"2011","journal-title":"Experimental cell research"},{"issue":"7492","key":"pcbi.1010039.ref032","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1038\/nature12972","article-title":"Intestinal crypt homeostasis revealed at single-stem-cell level by in vivo live imaging","volume":"507","author":"L Ritsma","year":"2014","journal-title":"Nature"},{"issue":"1","key":"pcbi.1010039.ref033","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1039\/C4IB00191E","article-title":"Cancer stem cells: small subpopulation or evolving fraction?","volume":"7","author":"H. Enderling","year":"2014","journal-title":"Integrative Biology."},{"issue":"7562","key":"pcbi.1010039.ref034","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/nature14553","article-title":"Parent stem cells can serve as niches for their daughter cells","volume":"523","author":"A Pardo-Saganta","year":"2015","journal-title":"Nature"},{"issue":"1","key":"pcbi.1010039.ref035","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s11538-012-9798-x","article-title":"The tumor growth paradox and immune system-mediated selection for cancer stem cells","volume":"75","author":"T Hillen","year":"2013","journal-title":"Bulletin of mathematical biology"},{"issue":"1","key":"pcbi.1010039.ref036","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrm2319","article-title":"No place like home: anatomy and function of the stem cell niche","volume":"9","author":"DL Jones","year":"2008","journal-title":"Nature reviews Molecular cell biology"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1010039","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T00:00:00Z","timestamp":1652832000000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010039","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T13:45:02Z","timestamp":1652881502000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010039"}},"subtitle":[],"editor":[{"given":"Feng","family":"Fu","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,5,6]]},"references-count":36,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5,6]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1010039","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.06.15.448623","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,6]]}}}