{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T07:41:54Z","timestamp":1791531714883,"version":"4.3.4"},"reference-count":44,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2020,1,1]],"date-time":"2020-01-01T00:00:00Z","timestamp":1577836800000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21DE022959"],"award-info":[{"award-number":["R21DE022959"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Salivary glands exert exocrine secretory function to provide saliva for lubrication and protection of the oral cavity. Its epithelium consists of several differentiated cell types including acinar, ductal and myoepithelial cells that are maintained in a lineage-restricted manner during homeostasis or after mild injuries. Glandular regeneration following a near complete loss of secretory cells, however, may involve cellular plasticity, although the mechanism and extent of such plasticity remain unclear. Here, by combining lineage-tracing experiments with a model of severe glandular injury in the mouse submandibular gland, we show that de novo formation of acini involves induction of cellular plasticity in multiple non-acinar cell populations. Fate-mapping analysis revealed that although ductal stem cells marked by cytokeratin K14 and Axin2 undergo a multipotency switch, they do not make a significant contribution to acinar regeneration. Intriguingly, more than 80% of regenerated acini derive from differentiated cells including myoepithelial and ductal cells that appear to dedifferentiate to a progenitor-like state before re-differentiation to acinar cells. The potential of diverse cell populations serving as a reserve source for acini widens the therapeutic options for hyposalivation.<\/jats:p>","DOI":"10.1242\/dev.192807","type":"journal-article","created":{"date-parts":[[2020,9,29]],"date-time":"2020-09-29T13:58:55Z","timestamp":1601387935000},"source":"Crossref","is-referenced-by-count":32,"title":["Diverse epithelial cell populations contribute to regeneration of secretory units in injured salivary glands"],"prefix":"10.1242","author":[{"given":"Ninche","family":"Ninche","sequence":"first","affiliation":[{"name":"Department of Oral Biology & Pathology, Stony Brook University, Stony Brook, NY 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyu","family":"Kwak","sequence":"additional","affiliation":[{"name":"Department of Oral Biology & Pathology, Stony Brook University, Stony Brook, NY 11794, USA"},{"name":"Current address: Section of Orthodontics, School of Dentistry, University of California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3260-3549","authenticated-orcid":false,"given":"Soosan","family":"Ghazizadeh","sequence":"additional","affiliation":[{"name":"Department of Oral Biology & Pathology, Stony Brook University, Stony Brook, NY 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2020,1,1]]},"reference":[{"key":"2021042700421447000_DEV192807C1","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1267\/ahc.12013","article-title":"Anatomy and histology of rodent and human major salivary glands: -overview of the Japan salivary gland society-sponsored workshop","volume":"45","author":"Amano","year":"2012","journal-title":"Acta Histochem. Cytochem."},{"key":"2021042700421447000_DEV192807C2","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1016\/j.stemcr.2019.01.002","article-title":"Sox10 Regulates plasticity of epithelial progenitors toward secretory units of exocrine glands","volume":"12","author":"Athwal","year":"2019","journal-title":"Stem Cell Reports"},{"key":"2021042700421447000_DEV192807C3","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.devcel.2015.02.013","article-title":"Salivary gland homeostasis is maintained through acinar cell self-duplication","volume":"33","author":"Aure","year":"2015","journal-title":"Dev. Cell"},{"key":"2021042700421447000_DEV192807C4","doi-asserted-by":"publisher","first-page":"1242281","DOI":"10.1126\/science.1242281","article-title":"Plasticity of epithelial stem cells in tissue regeneration","volume":"344","author":"Blanpain","year":"2014","journal-title":"Science"},{"key":"2021042700421447000_DEV192807C5","first-page":"153","article-title":"Cell death and cell proliferation in mouse submandibular gland during early post-irradiation phase","volume":"59","author":"Bralic","year":"2005","journal-title":"Acta Med. Okayama"},{"key":"2021042700421447000_DEV192807C6","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1016\/S1079-2104(98)90038-5","article-title":"Cell population changes during atrophy and regeneration of rat parotid gland","volume":"85","author":"Burgess","year":"1998","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod."},{"key":"2021042700421447000_DEV192807C7","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1146\/annurev-biochem-062917-012341","article-title":"Defining adult stem cells by function, not by phenotype","volume":"87","author":"Clevers","year":"2018","journal-title":"Annu. Rev. Biochem."},{"key":"2021042700421447000_DEV192807C8","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1007\/s00441-008-0588-6","article-title":"Early markers of regeneration following ductal ligation in rat submandibular gland","volume":"332","author":"Cotroneo","year":"2008","journal-title":"Cell Tissue Res."},{"key":"2021042700421447000_DEV192807C9","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.diff.2009.11.005","article-title":"Regeneration of acinar cells following ligation of rat submandibular gland retraces the embryonic-perinatal pathway of cytodifferentiation","volume":"79","author":"Cotroneo","year":"2010","journal-title":"Differentiation"},{"key":"2021042700421447000_DEV192807C10","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1177\/10454411970080010301","article-title":"Salivary glands: a paradigm for diversity of gland development","volume":"8","author":"Denny","year":"1997","journal-title":"Crit. Rev. Oral Biol. Med."},{"key":"2021042700421447000_DEV192807C11","doi-asserted-by":"publisher","first-page":"e26620","DOI":"10.7554\/eLife.26620","article-title":"SOX2 regulates acinar cell development in the salivary gland","volume":"6","author":"Emmerson","year":"2017","journal-title":"Elife"},{"key":"2021042700421447000_DEV192807C12","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1002\/stem.780","article-title":"In vivo fate mapping identifies mesenchymal progenitor cells","volume":"30","author":"Grcevic","year":"2012","journal-title":"Stem Cells"},{"key":"2021042700421447000_DEV192807C13","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1002\/hep.20063","article-title":"Flow cytometric isolation of endodermal progenitors from mouse salivary gland differentiate into hepatic and pancreatic lineages","volume":"39","author":"Hisatomi","year":"2004","journal-title":"Hepatology"},{"key":"2021042700421447000_DEV192807C14","doi-asserted-by":"publisher","first-page":"1630","DOI":"10.1038\/ncomms2626","article-title":"Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity","volume":"4","author":"Klein","year":"2013","journal-title":"Nat. Commun."},{"key":"2021042700421447000_DEV192807C15","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1038\/ncb3309","article-title":"Stem cells versus plasticity in liver and pancreas regeneration","volume":"18","author":"Kopp","year":"2016","journal-title":"Nat. Cell Biol."},{"key":"2021042700421447000_DEV192807C16","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1089\/scd.2014.0355","article-title":"Analysis of histone H2BGFP retention in mouse submandibular gland reveals actively dividing stem cell populations","volume":"24","author":"Kwak","year":"2015","journal-title":"Stem Cells Dev."},{"key":"2021042700421447000_DEV192807C17","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1177\/0022034516634664","article-title":"Identification of stem cells in the secretory complex of salivary glands","volume":"97","author":"Kwak","year":"2016","journal-title":"J. Dent. Res."},{"key":"2021042700421447000_DEV192807C18","doi-asserted-by":"publisher","first-page":"14193","DOI":"10.1038\/s41598-018-32557-1","article-title":"c-Kit+ cells in adult salivary glands do not function as tissue stem cells","volume":"8","author":"Kwak","year":"2018","journal-title":"Sci. Rep."},{"key":"2021042700421447000_DEV192807C19","doi-asserted-by":"publisher","first-page":"e2063","DOI":"10.1371\/journal.pone.0002063","article-title":"Rescue of salivary gland function after stem cell transplantation in irradiated glands","volume":"3","author":"Lombaert","year":"2008","journal-title":"PLoS ONE"},{"key":"2021042700421447000_DEV192807C20","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1016\/j.stemcr.2013.10.013","article-title":"Combined KIT and FGFR2b signaling regulates epithelial progenitor expansion during organogenesis","volume":"1","author":"Lombaert","year":"2013","journal-title":"Stem Cell Reports"},{"key":"2021042700421447000_DEV192807C21","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.cell.2012.04.045","article-title":"Identification of stem cell populations in sweat glands and ducts reveals roles in homeostasis and wound repair","volume":"150","author":"Lu","year":"2012","journal-title":"Cell"},{"key":"2021042700421447000_DEV192807C22","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/j.stem.2018.03.017","article-title":"Submucosal gland myoepithelial cells are reserve stem cells that can regenerate mouse tracheal epithelium","volume":"22","author":"Lynch","year":"2018","journal-title":"Cell Stem Cell"},{"key":"2021042700421447000_DEV192807C23","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1038\/jid.2009.244","article-title":"Regeneration of multilineage skin epithelia by differentiated keratinocytes","volume":"130","author":"Mannik","year":"2010","journal-title":"J. Invest. Dermatol."},{"key":"2021042700421447000_DEV192807C24","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1016\/0003-9969(82)90082-6","article-title":"Progressive secretory dysfunction in the rat submandibular gland after excretory duct ligation","volume":"27","author":"Martinez","year":"1982","journal-title":"Arch. Oral Biol."},{"key":"2021042700421447000_DEV192807C25","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1038\/nature11393","article-title":"Distinct contribution of stem and progenitor cells to epidermal maintenance","volume":"489","author":"Mascre","year":"2012","journal-title":"Nature"},{"key":"2021042700421447000_DEV192807C26","doi-asserted-by":"publisher","first-page":"dev166363","DOI":"10.1242\/dev.166363","article-title":"Diverse progenitor cells preserve salivary gland ductal architecture after radiation-induced damage","volume":"145","author":"May","year":"2018","journal-title":"Development"},{"key":"2021042700421447000_DEV192807C27","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1038\/nrm.2016.24","article-title":"Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style","volume":"17","author":"Merrell","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2021042700421447000_DEV192807C28","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/S0079-6336(03)80001-3","article-title":"Immunocytochemistry of myoepithelial cells in the salivary glands","volume":"38","author":"Ogawa","year":"2003","journal-title":"Prog. Histochem. Cytochem."},{"key":"2021042700421447000_DEV192807C29","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.1038\/modpathol.2013.54","article-title":"SOX10 is a novel marker of acinus and intercalated duct differentiation in salivary gland tumors: a clue to the histogenesis for tumor diagnosis","volume":"26","author":"Ohtomo","year":"2013","journal-title":"Mod. Pathol."},{"key":"2021042700421447000_DEV192807C30","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1038\/ncb3025","article-title":"Mammary stem cells have myoepithelial cell properties","volume":"16","author":"Prater","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"2021042700421447000_DEV192807C31","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.autneu.2006.10.006","article-title":"Regulation of salivary gland function by autonomic nerves","volume":"133","author":"Proctor","year":"2007","journal-title":"Auton. Neurosci."},{"key":"2021042700421447000_DEV192807C32","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1002\/jemt.1070270103","article-title":"Myoepithelium of salivary glands","volume":"27","author":"Redman","year":"1994","journal-title":"Microsc. Res. Tech."},{"key":"2021042700421447000_DEV192807C33","doi-asserted-by":"publisher","first-page":"14043","DOI":"10.1038\/s41598-018-32343-z","article-title":"Genetic and scRNA-seq analysis reveals distinct cell populations that contribute to salivary gland development and maintenance","volume":"8","author":"Song","year":"2018","journal-title":"Sci. Rep."},{"key":"2021042700421447000_DEV192807C34","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1046\/j.1365-2613.1998.710405.x","article-title":"Origin of acinar cell regeneration after atrophy of the rat parotid induced by duct obstruction","volume":"79","author":"Takahashi","year":"1998","journal-title":"Int. J. Exp. Pathol."},{"key":"2021042700421447000_DEV192807C35","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1046\/j.1365-2613.1999.00124.x","article-title":"Changing myoepithelial cell distribution during regeneration of rat parotid glands","volume":"80","author":"Takahashi","year":"1999","journal-title":"Int. J. Exp. Pathol."},{"key":"2021042700421447000_DEV192807C36","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/S0040-8166(00)80002-6","article-title":"Apoptosis and mitosis of parenchymal cells in the duct-ligated rat submandibular gland","volume":"32","author":"Takahashi","year":"2000","journal-title":"Tissue Cell"},{"key":"2021042700421447000_DEV192807C37","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1111\/j.1600-0714.2004.00234.x","article-title":"Mitotic proliferation of myoepithelial cells during regeneration of atrophied rat submandibular glands after duct ligation","volume":"33","author":"Takahashi","year":"2004","journal-title":"J. Oral Pathol. Med."},{"key":"2021042700421447000_DEV192807C38","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1111\/j.1600-0714.2004.00191.x","article-title":"Cell death and cell proliferation in the regeneration of atrophied rat submandibular glands after duct ligation","volume":"33","author":"Takahashi","year":"2004","journal-title":"J. Oral Pathol. Med."},{"key":"2021042700421447000_DEV192807C39","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1016\/j.stem.2018.03.018","article-title":"Myoepithelial cells of submucosal glands can function as reserve stem cells to regenerate airways after injury","volume":"22","author":"Tata","year":"2018","journal-title":"Cell Stem Cell"},{"key":"2021042700421447000_DEV192807C40","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1126\/science.1092436","article-title":"Defining the epithelial stem cell niche in skin","volume":"303","author":"Tumbar","year":"2004","journal-title":"Science"},{"key":"2021042700421447000_DEV192807C41","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/j.arcmed.2005.03.005","article-title":"Early and late effects of x-irradiation on submandibular gland: a morphological study in mice","volume":"36","author":"Urek","year":"2005","journal-title":"Arch. Med. Res."},{"key":"2021042700421447000_DEV192807C42","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1002\/path.1711530407","article-title":"Cell death and cell proliferation during atrophy of the rat parotid gland induced by duct obstruction","volume":"153","author":"Walker","year":"1987","journal-title":"J. Pathol."},{"key":"2021042700421447000_DEV192807C43","doi-asserted-by":"publisher","first-page":"1464","DOI":"10.1016\/j.celrep.2018.07.016","article-title":"Limited regeneration of adult salivary glands after severe injury involves cellular plasticity","volume":"24","author":"Weng","year":"2018","journal-title":"Cell Rep."},{"key":"2021042700421447000_DEV192807C44","doi-asserted-by":"publisher","first-page":"3364","DOI":"10.1172\/JCI74096","article-title":"Neurotrophic factor GDNF promotes survival of salivary stem cells","volume":"124","author":"Xiao","year":"2014","journal-title":"J. Clin. Invest."}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/dev.192807","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.192807\/1967937\/dev192807.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.192807\/2065289\/dev_192807v1.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.192807\/2065289\/dev_192807v1.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T18:52:08Z","timestamp":1621363928000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/doi\/10.1242\/dev.192807\/267033\/Diverse-epithelial-cell-populations-contribute-to"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,1]]},"references-count":44,"URL":"https:\/\/doi.org\/10.1242\/dev.192807","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.06.29.177733","asserted-by":"object"}]},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2020,1,1]]},"article-number":"dev.192807"}}