{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T12:57:37Z","timestamp":1792155457445,"version":"4.4.0"},"reference-count":41,"publisher":"Association for Research in Vision and Ophthalmology (ARVO)","issue":"14","license":[{"start":{"date-parts":[[2018,11,27]],"date-time":"2018-11-27T00:00:00Z","timestamp":1543276800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Invest. Ophthalmol. Vis. Sci."],"published-print":{"date-parts":[[2018,11,27]]},"DOI":"10.1167\/iovs.17-23576","type":"journal-article","created":{"date-parts":[[2018,11,27]],"date-time":"2018-11-27T18:00:47Z","timestamp":1543341647000},"page":"DES169","source":"Crossref","is-referenced-by-count":21,"title":["Regeneration of Lacrimal Gland Function to Maintain the Health of the Ocular Surface"],"prefix":"10.1167","volume":"59","author":[{"given":"Tetsuya","family":"Kawakita","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan"},{"name":"Department of Ophthalmology, Kitasato University Kitasato Institute Hospital, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"27","reference":[{"key":"i1552-5783-59-14-DES169-b01","unstructured":"Thoft RA, Friend J. The X, Y, Z hypothesis of corneal epithelial maintenance. Invest Ophthalmol Vis Sci. 1983; 24: 1442\u2013 1443."},{"key":"i1552-5783-59-14-DES169-b02","doi-asserted-by":"crossref","unstructured":"Tseng SC. Concept and application of limbal stem cells. Eye (Lond). 1989; 3 (pt 2): 141\u2013 157.","DOI":"10.1038\/eye.1989.22"},{"key":"i1552-5783-59-14-DES169-b03","doi-asserted-by":"crossref","unstructured":"Yao Y, Zhang Y. The lacrimal gland: development, wound repair and regeneration. Biotechnol Lett. 2017; 39: 939\u2013 949.","DOI":"10.1007\/s10529-017-2326-1"},{"key":"i1552-5783-59-14-DES169-b04","doi-asserted-by":"crossref","unstructured":"Wakamatsu TH, Sant'Anna A, Cristovam PC, Alves VAF, Wakamatsu A, Gomes JAP. Minor salivary gland transplantation for severe dry eyes. Cornea. 2017; 36 (suppl 1): S26\u2013 S33.","DOI":"10.1097\/ICO.0000000000001358"},{"key":"i1552-5783-59-14-DES169-b05","doi-asserted-by":"crossref","unstructured":"You S, Kublin CL, Avidan O, Miyasaki D, Zoukhri D. Isolation and propagation of mesenchymal stem cells from the lacrimal gland. Invest Ophthalmol Vis Sci. 2011; 52: 2087\u2013 2094.","DOI":"10.1167\/iovs.10-5686"},{"key":"i1552-5783-59-14-DES169-b06","doi-asserted-by":"crossref","unstructured":"Yaguchi S, Ogawa Y, Kawakita T, Shimmura S, Tsubota K. Tissue renin-angiotensin system in lacrimal gland fibrosis in a murine model of chronic graft-versus-host disease. Cornea. 2015; 34 (suppl 11): S142\u2013 S152.","DOI":"10.1097\/ICO.0000000000000586"},{"key":"i1552-5783-59-14-DES169-b07","unstructured":"Tuchocka-Piotrowska A, Puszczewicz M, Kolczewska A, Majewski D. Graft-versus-host disease as the cause of symptoms mimicking Sjogren's syndrome [in Polish]. Ann Acad Med Stetin. 2006; 52 (suppl 2): 89\u2013 93."},{"key":"i1552-5783-59-14-DES169-b08","doi-asserted-by":"crossref","unstructured":"Kawai M, Ogawa Y, Shimmura S, et al. Expression and localization of aging markers in lacrimal gland of chronic graft-versus-host disease. Sci Rep. 2013; 3: 2455.","DOI":"10.1038\/srep02455"},{"key":"i1552-5783-59-14-DES169-b09","doi-asserted-by":"crossref","unstructured":"Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest. 2002; 110: 341\u2013 350.","DOI":"10.1172\/JCI0215518"},{"key":"i1552-5783-59-14-DES169-b10","doi-asserted-by":"crossref","unstructured":"Chilosi M, Poletti V, Zamo A, et al. Aberrant Wnt\/beta-catenin pathway activation in idiopathic pulmonary fibrosis. Am J Pathol. 2003; 162: 1495\u2013 1502.","DOI":"10.1016\/S0002-9440(10)64282-4"},{"key":"i1552-5783-59-14-DES169-b11","doi-asserted-by":"crossref","unstructured":"Stone RC, Pastar I, Ojeh N, et al. Epithelial-mesenchymal transition in tissue repair and fibrosis. Cell Tissue Res. 2016; 365: 495\u2013 506.","DOI":"10.1007\/s00441-016-2464-0"},{"key":"i1552-5783-59-14-DES169-b12","doi-asserted-by":"crossref","unstructured":"Liao TT, Yang MH. Revisiting epithelial-mesenchymal transition in cancer metastasis: the connection between epithelial plasticity and stemness. Mol Oncol. 2017; 11: 792\u2013 804.","DOI":"10.1002\/1878-0261.12096"},{"key":"i1552-5783-59-14-DES169-b13","doi-asserted-by":"crossref","unstructured":"Shintani Y, Maeda M, Chaika N, Johnson KR, Wheelock MJ. Collagen I promotes epithelial-to-mesenchymal transition in lung cancer cells via transforming growth factor-beta signaling. Am J Respir Cell Mol Biol. 2008; 38: 95\u2013 104.","DOI":"10.1165\/rcmb.2007-0071OC"},{"key":"i1552-5783-59-14-DES169-b14","doi-asserted-by":"crossref","unstructured":"Shu DY, Lovicu FJ. Myofibroblast transdifferentiation: the dark force in ocular wound healing and fibrosis. Prog Retin Eye Res. 2017; 60: 44\u2013 65.","DOI":"10.1016\/j.preteyeres.2017.08.001"},{"key":"i1552-5783-59-14-DES169-b15","doi-asserted-by":"crossref","unstructured":"Redman RS. Myoepithelium of salivary glands. Microsc Res Tech. 1994; 27: 25\u2013 45.","DOI":"10.1002\/jemt.1070270103"},{"key":"i1552-5783-59-14-DES169-b16","doi-asserted-by":"crossref","unstructured":"Ogawa Y, Shimmura S, Kawakita T, Yoshida S, Kawakami Y, Tsubota K. Epithelial mesenchymal transition in human ocular chronic graft-versus-host disease. Am J Pathol. 2009; 175: 2372\u2013 2381.","DOI":"10.2353\/ajpath.2009.090318"},{"key":"i1552-5783-59-14-DES169-b17","doi-asserted-by":"crossref","unstructured":"Zoukhri D, Macari E, Kublin CL. A single injection of interleukin-1 induces reversible aqueous-tear deficiency, lacrimal gland inflammation, and acinar and ductal cell proliferation. Exp Eye Res. 2007; 84: 894\u2013 904.","DOI":"10.1016\/j.exer.2007.01.015"},{"key":"i1552-5783-59-14-DES169-b18","doi-asserted-by":"crossref","unstructured":"You S, Avidan O, Tariq A, et al. Role of epithelial-mesenchymal transition in repair of the lacrimal gland after experimentally induced injury. Invest Ophthalmol Vis Sci. 2012; 53: 126\u2013 135.","DOI":"10.1167\/iovs.11-7893"},{"key":"i1552-5783-59-14-DES169-b19","doi-asserted-by":"crossref","unstructured":"Zoukhri D, Fix A, Alroy J, Kublin CL. Mechanisms of murine lacrimal gland repair after experimentally induced inflammation. Invest Ophthalmol Vis Sci. 2008; 49: 4399\u2013 4406.","DOI":"10.1167\/iovs.08-1730"},{"key":"i1552-5783-59-14-DES169-b20","doi-asserted-by":"crossref","unstructured":"Tag CG, Sauer-Lehnen S, Weiskirchen S, et al. Bile duct ligation in mice: induction of inflammatory liver injury and fibrosis by obstructive cholestasis. J Vis Exp. 2015; 96: 52438.","DOI":"10.3791\/52438"},{"key":"i1552-5783-59-14-DES169-b21","doi-asserted-by":"crossref","unstructured":"Takahashi S, Shinzato K, Nakamura S, Domon T, Yamamoto T, Wakita M. The roles of apoptosis and mitosis in atrophy of the rat sublingual gland. Tissue Cell. 2002; 34: 297\u2013 304.","DOI":"10.1016\/S0040816602000034"},{"key":"i1552-5783-59-14-DES169-b22","doi-asserted-by":"crossref","unstructured":"Scoggins CR, Meszoely IM, Wada M, Means AL, Yang L, Leach SD. p53-dependent acinar cell apoptosis triggers epithelial proliferation in duct-ligated murine pancreas. Am J Physiol Gastrointest Liver Physiol. 2000; 279: G827\u2013 G836.","DOI":"10.1152\/ajpgi.2000.279.4.G827"},{"key":"i1552-5783-59-14-DES169-b23","doi-asserted-by":"crossref","unstructured":"Cotroneo E, Proctor GB, Carpenter GH. Regeneration of acinar cells following ligation of rat submandibular gland retraces the embryonic-perinatal pathway of cytodifferentiation. Differentiation. 2010; 79: 120\u2013 130.","DOI":"10.1016\/j.diff.2009.11.005"},{"key":"i1552-5783-59-14-DES169-b24","doi-asserted-by":"crossref","unstructured":"Liu Y, Hirayama M, Kawakita T, Tsubota K. A ligation of the lacrimal excretory duct in mouse induces lacrimal gland inflammation with proliferative cells. Stem Cells Int. 2017; 2017: 4923426.","DOI":"10.1155\/2017\/4923426"},{"key":"i1552-5783-59-14-DES169-b25","doi-asserted-by":"crossref","unstructured":"Lin H, Liu Y, He H, Botsford B, Yiu S. Lacrimal gland repair after short-term obstruction of excretory duct in rabbits. Sci Rep. 2017; 7: 8290.","DOI":"10.1038\/s41598-017-08197-2"},{"key":"i1552-5783-59-14-DES169-b26","doi-asserted-by":"crossref","unstructured":"Galili D, Maller O, Brightman VJ. The effects of desalivation by duct ligation or salivary gland extirpation on taste preference in rats. Arch Oral Biol. 1981; 26: 853\u2013 858.","DOI":"10.1016\/0003-9969(81)90142-4"},{"key":"i1552-5783-59-14-DES169-b27","doi-asserted-by":"crossref","unstructured":"Lombaert IM, Brunsting JF, Wierenga PK, et al. Rescue of salivary gland function after stem cell transplantation in irradiated glands. PLoS One. 2008; 3: e2063.","DOI":"10.1371\/journal.pone.0002063"},{"key":"i1552-5783-59-14-DES169-b28","doi-asserted-by":"crossref","unstructured":"Pringle S, Maimets M, van der Zwaag M, et al. Human salivary gland stem cells functionally restore radiation damaged salivary glands. Stem Cells. 2016; 34: 640\u2013 652.","DOI":"10.1002\/stem.2278"},{"key":"i1552-5783-59-14-DES169-b29","doi-asserted-by":"crossref","unstructured":"Gromova A, Voronov DA, Yoshida M, et al. Lacrimal gland repair using progenitor cells. Stem Cells Transl Med. 2017; 6: 88\u2013 98.","DOI":"10.5966\/sctm.2016-0191"},{"key":"i1552-5783-59-14-DES169-b30","unstructured":"Kobayashi S, Kawakita T, Kawashima M, et al. Characterization of cultivated murine lacrimal gland epithelial cells. Mol Vis. 2012; 18: 1271\u2013 1277."},{"key":"i1552-5783-59-14-DES169-b31","doi-asserted-by":"crossref","unstructured":"Umazume T, Thomas WM, Campbell S, et al. Lacrimal gland inflammation deregulates extracellular matrix remodeling and alters molecular signature of epithelial stem\/progenitor cells. Invest Ophthalmol Vis Sci. 2015; 56: 8392\u2013 8402.","DOI":"10.1167\/iovs.15-17477"},{"key":"i1552-5783-59-14-DES169-b32","doi-asserted-by":"crossref","unstructured":"Mishima K, Inoue H, Nishiyama T, et al. Transplantation of side population cells restores the function of damaged exocrine glands through clusterin. Stem Cells. 2012; 30: 1925\u2013 1937.","DOI":"10.1002\/stem.1173"},{"key":"i1552-5783-59-14-DES169-b33","doi-asserted-by":"crossref","unstructured":"Pflugfelder SC, Tseng SC, Sanabria O, et al. Evaluation of subjective assessments and objective diagnostic tests for diagnosing tear-film disorders known to cause ocular irritation. Cornea. 1998; 17: 38\u2013 56.","DOI":"10.1097\/00003226-199801000-00007"},{"key":"i1552-5783-59-14-DES169-b34","doi-asserted-by":"crossref","unstructured":"Stern ME, Beuerman RW, Fox RI, Gao J, Mircheff AK, Pflugfelder SC. The pathology of dry eye: the interaction between the ocular surface and lacrimal glands. Cornea. 1998; 17: 584\u2013 589.","DOI":"10.1097\/00003226-199811000-00002"},{"key":"i1552-5783-59-14-DES169-b35","doi-asserted-by":"crossref","unstructured":"Willshire C, Buckley RJ, Bron AJ. Central connections of the lacrimal functional unit. Cornea. 2017; 36: 898\u2013 907.","DOI":"10.1097\/ICO.0000000000001250"},{"key":"i1552-5783-59-14-DES169-b36","doi-asserted-by":"crossref","unstructured":"Lombaert I, Movahednia MM, Adine C, Ferreira JN. Concise review: salivary gland regeneration: therapeutic approaches from stem cells to tissue organoids. Stem Cells. 2017; 35: 97\u2013 105.","DOI":"10.1002\/stem.2455"},{"key":"i1552-5783-59-14-DES169-b37","doi-asserted-by":"crossref","unstructured":"Hirayama M, Ogawa M, Oshima M, et al. Functional lacrimal gland regeneration by transplantation of a bioengineered organ germ. Nat Commun. 2013; 4: 2497.","DOI":"10.1038\/ncomms3497"},{"key":"i1552-5783-59-14-DES169-b38","doi-asserted-by":"crossref","unstructured":"Hirayama M, Kawakita T, Tsubota K, Shimmura S. Challenges and strategies for regenerating the lacrimal gland. Ocul Surf. 2016; 14: 135\u2013 143.","DOI":"10.1016\/j.jtos.2015.11.005"},{"key":"i1552-5783-59-14-DES169-b39","doi-asserted-by":"crossref","unstructured":"Sant' Anna AE, Hazarbassanov RM, de Freitas D, Gomes JA . Minor salivary glands and labial mucous membrane graft in the treatment of severe symblepharon and dry eye in patients with Stevens-Johnson syndrome. Br J Ophthalmol. 2012; 96: 234\u2013 239.","DOI":"10.1136\/bjo.2010.199901"},{"key":"i1552-5783-59-14-DES169-b40","doi-asserted-by":"crossref","unstructured":"Graf T, Enver T. Forcing cells to change lineages. Nature. 2009; 462: 587\u2013 594.","DOI":"10.1038\/nature08533"},{"key":"i1552-5783-59-14-DES169-b41","doi-asserted-by":"crossref","unstructured":"Hirayama M, Ko SBH, Kawakita T, et al. Identification of transcription factors that promote the differentiation of human pluripotent stem cells into lacrimal gland epithelium-like cells. NPJ Aging Mech Dis. 2017; 3: 1.","DOI":"10.1038\/s41514-016-0001-8"}],"container-title":["Investigative Opthalmology & Visual Science"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/iovs.arvojournals.org\/article.aspx?articleid=2717237","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:30:51Z","timestamp":1791927051000},"score":1,"resource":{"primary":{"URL":"http:\/\/iovs.arvojournals.org\/article.aspx?doi=10.1167\/iovs.17-23576"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,27]]},"references-count":41,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2018,11,1]]}},"URL":"https:\/\/doi.org\/10.1167\/iovs.17-23576","relation":{},"ISSN":["1552-5783"],"issn-type":[{"value":"1552-5783","type":"print"}],"subject":[],"published":{"date-parts":[[2018,11,27]]}}}