{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:57:43Z","timestamp":1791928663857,"version":"4.3.4"},"reference-count":106,"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.17-23528","type":"journal-article","created":{"date-parts":[[2018,11,27]],"date-time":"2018-11-27T18:00:46Z","timestamp":1543341646000},"page":"DES174","source":"Crossref","is-referenced-by-count":13,"title":["Advances in Functional Restoration of the Lacrimal Glands"],"prefix":"10.1167","volume":"59","author":[{"given":"Masatoshi","family":"Hirayama","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan"},{"name":"Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"27","reference":[{"key":"i1552-5783-59-14-DES174-b01","doi-asserted-by":"crossref","unstructured":"Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II definition and classification report. Ocul Surf. 2017; 15: 276\u2013 283.","DOI":"10.1016\/j.jtos.2017.05.008"},{"key":"i1552-5783-59-14-DES174-b02","doi-asserted-by":"crossref","unstructured":"Schechter JE, Warren DW, Mircheff AK. A lacrimal gland is a lacrimal gland, but rodent's and rabbit's are not human. Ocul Surf. 2010; 8: 111\u2013 134.","DOI":"10.1016\/S1542-0124(12)70222-7"},{"key":"i1552-5783-59-14-DES174-b03","doi-asserted-by":"crossref","unstructured":"Tiwari S, Ali MJ, Balla MM, et al. Establishing human lacrimal gland cultures with secretory function. PLoS One. 2012; 7: e29458.","DOI":"10.1371\/journal.pone.0029458"},{"key":"i1552-5783-59-14-DES174-b04","doi-asserted-by":"crossref","unstructured":"Mishima S. Some physiological aspects of the precorneal tear film. Arch Ophthalmol. 1965; 73: 233\u2013 241.","DOI":"10.1001\/archopht.1965.00970030235017"},{"key":"i1552-5783-59-14-DES174-b05","doi-asserted-by":"crossref","unstructured":"Kojima T, Higuchi A, Goto E, Matsumoto Y, Dogru M, Tsubota K. Autologous serum eye drops for the treatment of dry eye diseases. Cornea. 2008; 27 (suppl 1): S25\u2013 S30.","DOI":"10.1097\/ICO.0b013e31817f3a0e"},{"key":"i1552-5783-59-14-DES174-b06","doi-asserted-by":"crossref","unstructured":"Kojima T, Ishida R, Dogru M, et al. The effect of autologous serum eyedrops in the treatment of severe dry eye disease: a prospective randomized case-control study. Am J Ophthalmol. 2005; 139: 242\u2013 246.","DOI":"10.1016\/j.ajo.2004.08.040"},{"key":"i1552-5783-59-14-DES174-b07","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-DES174-b08","doi-asserted-by":"crossref","unstructured":"Atala A. Tissue engineering, stem cells and cloning: current concepts and changing trends. Expert Opin Biol Ther. 2005; 5: 879\u2013 892.","DOI":"10.1517\/14712598.5.7.879"},{"key":"i1552-5783-59-14-DES174-b09","doi-asserted-by":"crossref","unstructured":"Brockes JP, Kumar A. Appendage regeneration in adult vertebrates and implications for regenerative medicine. Science. 2005; 310: 1919\u2013 1923.","DOI":"10.1126\/science.1115200"},{"key":"i1552-5783-59-14-DES174-b10","doi-asserted-by":"crossref","unstructured":"Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006; 354: 1813\u2013 1826.","DOI":"10.1056\/NEJMra052638"},{"key":"i1552-5783-59-14-DES174-b11","doi-asserted-by":"crossref","unstructured":"Segers VF, Lee RT. Stem-cell therapy for cardiac disease. Nature. 2008; 451: 937\u2013 942.","DOI":"10.1038\/nature06800"},{"key":"i1552-5783-59-14-DES174-b12","doi-asserted-by":"crossref","unstructured":"Wang X, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Grompe M. The origin and liver repopulating capacity of murine oval cells. Proc Natl Acad Sci U S A. 2003; 100 (suppl 1): 11881\u2013 11888.","DOI":"10.1073\/pnas.1734199100"},{"key":"i1552-5783-59-14-DES174-b13","doi-asserted-by":"crossref","unstructured":"Nishida K, Yamato M, Hayashida Y, et al. Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium. N Engl J Med. 2004; 351: 1187\u2013 1196.","DOI":"10.1056\/NEJMoa040455"},{"key":"i1552-5783-59-14-DES174-b14","doi-asserted-by":"crossref","unstructured":"Hirayama M, Satake Y, Higa K, Yamaguchi T, Shimazaki J. Transplantation of cultivated oral mucosal epithelium prepared in fibrin-coated culture dishes. Invest Ophthalmol Vis Sci. 2012; 53: 1602\u2013 1609.","DOI":"10.1167\/iovs.11-7847"},{"key":"i1552-5783-59-14-DES174-b15","doi-asserted-by":"crossref","unstructured":"Shimazaki J, Aiba M, Goto E, Kato N, Shimmura S, Tsubota K. Transplantation of human limbal epithelium cultivated on amniotic membrane for the treatment of severe ocular surface disorders. Ophthalmology. 2002; 109: 1285\u2013 1290.","DOI":"10.1016\/S0161-6420(02)01089-8"},{"key":"i1552-5783-59-14-DES174-b16","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-DES174-b17","doi-asserted-by":"crossref","unstructured":"Hirayama M, Tsubota K, Tsuji T. Functional lacrimal gland regeneration toward a next-generation organ replacement therapy. Intern Med Review. 2017. Available at: https:\/\/www.internalmedicinereview.org\/index.php\/imr\/article\/view\/501.","DOI":"10.18103\/imr.v3i8.501"},{"key":"i1552-5783-59-14-DES174-b18","doi-asserted-by":"crossref","unstructured":"Abouna GM. Organ shortage crisis: problems and possible solutions. Transplant Proc. 2008; 40: 34\u2013 38.","DOI":"10.1016\/j.transproceed.2007.11.067"},{"key":"i1552-5783-59-14-DES174-b19","doi-asserted-by":"crossref","unstructured":"Zakrzewski JL, van den Brink MR, Hubbell JA. Overcoming immunological barriers in regenerative medicine. Nat Biotechnol. 2014; 32: 786\u2013 794.","DOI":"10.1038\/nbt.2960"},{"key":"i1552-5783-59-14-DES174-b20","doi-asserted-by":"crossref","unstructured":"Tsubota K, Satake Y, Kaido M, et al. Treatment of severe ocular-surface disorders with corneal epithelial stem-cell transplantation. N Engl J Med. 1999; 340: 1697\u2013 1703.","DOI":"10.1056\/NEJM199906033402201"},{"key":"i1552-5783-59-14-DES174-b21","doi-asserted-by":"crossref","unstructured":"Hirayama M, Yamaguchi T, Satake Y, Shimazaki J. Surgical outcome of Descemet's stripping automated endothelial keratoplasty for bullous keratopathy secondary to argon laser iridotomy. Graefes Arch Clin Exp Ophthalmol. 2012; 250: 1043\u2013 1050.","DOI":"10.1007\/s00417-012-1927-6"},{"key":"i1552-5783-59-14-DES174-b22","doi-asserted-by":"crossref","unstructured":"Hirayama M, Murat D, Liu Y, Kojima T, Kawakita T, Tsubota K. Efficacy of a novel moist cool air device in office workers with dry eye disease. Acta Ophthalmol. 2013; 91: 756\u2013 762.","DOI":"10.1111\/j.1755-3768.2012.02485.x"},{"key":"i1552-5783-59-14-DES174-b23","doi-asserted-by":"crossref","unstructured":"Oshima M, Inoue K, Nakajima K, et al. Functional tooth restoration by next-generation bio-hybrid implant as a bio-hybrid artificial organ replacement therapy. Sci Rep. 2014; 4: 6044.","DOI":"10.1038\/srep06044"},{"key":"i1552-5783-59-14-DES174-b24","doi-asserted-by":"crossref","unstructured":"Colton CK. Implantable biohybrid artificial organs. Cell Transplant. 1995; 4: 415\u2013 436.","DOI":"10.1177\/096368979500400413"},{"key":"i1552-5783-59-14-DES174-b25","doi-asserted-by":"crossref","unstructured":"Fort A, Fort N, Ricordi C, Stabler CL. Biohybrid devices and encapsulation technologies for engineering a bioartificial pancreas. Cell Transplant. 2008; 17: 997\u2013 1003.","DOI":"10.3727\/096368908786991498"},{"key":"i1552-5783-59-14-DES174-b26","doi-asserted-by":"crossref","unstructured":"Nakao K, Morita R, Saji Y, et al. The development of a bioengineered organ germ method. Nat Methods. 2007; 4: 227\u2013 230.","DOI":"10.1038\/nmeth1012"},{"key":"i1552-5783-59-14-DES174-b27","doi-asserted-by":"crossref","unstructured":"Ikeda E, Morita R, Nakao K, et al. Fully functional bioengineered tooth replacement as an organ replacement therapy. Proc Natl Acad Sci U S A. 2009; 106: 13475\u2013 13480.","DOI":"10.1073\/pnas.0902944106"},{"key":"i1552-5783-59-14-DES174-b28","doi-asserted-by":"crossref","unstructured":"Dartt DA. Tear lipocalin: structure and function. Ocul Surf. 2011; 9: 126\u2013 138.","DOI":"10.1016\/S1542-0124(11)70022-2"},{"key":"i1552-5783-59-14-DES174-b29","doi-asserted-by":"crossref","unstructured":"Ohashi Y, Dogru M, Tsubota K. Laboratory findings in tear fluid analysis. Clin Chim Acta. 2006; 369: 17\u2013 28.","DOI":"10.1016\/j.cca.2005.12.035"},{"key":"i1552-5783-59-14-DES174-b30","doi-asserted-by":"crossref","unstructured":"Tsubota K, Satake Y, Shimazaki J. Treatment of severe dry eye. Lancet. 1996; 348: 123.","DOI":"10.1016\/S0140-6736(96)24028-0"},{"key":"i1552-5783-59-14-DES174-b31","doi-asserted-by":"crossref","unstructured":"Dartt DA. Neural regulation of lacrimal gland secretory processes: relevance in dry eye diseases. Prog Retin Eye Res. 2009; 28: 155\u2013 177.","DOI":"10.1016\/j.preteyeres.2009.04.003"},{"key":"i1552-5783-59-14-DES174-b32","doi-asserted-by":"crossref","unstructured":"Dartt DA. Dysfunctional neural regulation of lacrimal gland secretion and its role in the pathogenesis of dry eye syndromes. Ocul Surf. 2004; 2: 76\u2013 91.","DOI":"10.1016\/S1542-0124(12)70146-5"},{"key":"i1552-5783-59-14-DES174-b33","doi-asserted-by":"crossref","unstructured":"Belmonte C, Nichols JJ, Cox SM, et al. TFOS DEWS II pain and sensation report. Ocul Surf. 2017; 15: 404\u2013 437.","DOI":"10.1016\/j.jtos.2017.05.002"},{"key":"i1552-5783-59-14-DES174-b34","doi-asserted-by":"crossref","unstructured":"Gomes JAP, Azar DT, Baudouin C, et al. TFOS DEWS II iatrogenic report. Ocul Surf. 2017; 15: 511\u2013 538.","DOI":"10.1016\/j.jtos.2017.05.004"},{"key":"i1552-5783-59-14-DES174-b35","doi-asserted-by":"crossref","unstructured":"Ogawa M, Oshima M, Imamura A, et al. Functional salivary gland regeneration by transplantation of a bioengineered organ germ. Nat Commun. 2013; 4: 2498.","DOI":"10.1038\/ncomms3498"},{"key":"i1552-5783-59-14-DES174-b36","doi-asserted-by":"crossref","unstructured":"Hirayama M, Tsubota K, Tsuji T. Bioengineered lacrimal gland organ regeneration in vivo. J Funct Biomater. 2015; 6: 634\u2013 649.","DOI":"10.3390\/jfb6030634"},{"key":"i1552-5783-59-14-DES174-b37","doi-asserted-by":"crossref","unstructured":"Oshima M, Mizuno M, Imamura A, et al. Functional tooth regeneration using a bioengineered tooth unit as a mature organ replacement regenerative therapy. PLoS One. 2011; 6: e21531.","DOI":"10.1371\/journal.pone.0021531"},{"key":"i1552-5783-59-14-DES174-b38","doi-asserted-by":"crossref","unstructured":"Makarenkova HP, Ito M, Govindarajan V, et al. FGF10 is an inducer and Pax6 a competence factor for lacrimal gland development. Development. 2000; 127: 2563\u2013 2572.","DOI":"10.1242\/dev.127.12.2563"},{"key":"i1552-5783-59-14-DES174-b39","doi-asserted-by":"crossref","unstructured":"Hogan BL, Grindley J, Bellusci S, Dunn NR, Emoto H, Itoh N. Branching morphogenesis of the lung: new models for a classical problem. Cold Spring Harb Symp Quant Biol. 1997; 62: 249\u2013 256.","DOI":"10.1101\/SQB.1997.062.01.031"},{"key":"i1552-5783-59-14-DES174-b40","doi-asserted-by":"crossref","unstructured":"Hogan BL, Yingling JM. Epithelial\/mesenchymal interactions and branching morphogenesis of the lung. Curr Opin Genet Dev. 1998; 8: 481\u2013 486.","DOI":"10.1016\/S0959-437X(98)80121-4"},{"key":"i1552-5783-59-14-DES174-b41","doi-asserted-by":"crossref","unstructured":"Sakai T. Epithelial branching morphogenesis of salivary gland: exploration of new functional regulators. J Med Invest. 2009; 56 (suppl): 234\u2013 238.","DOI":"10.2152\/jmi.56.234"},{"key":"i1552-5783-59-14-DES174-b42","doi-asserted-by":"crossref","unstructured":"Makarenkova HP, Hoffman MP, Beenken A, et al. Differential interactions of FGFs with heparan sulfate control gradient formation and branching morphogenesis. Sci Signal. 2009; 2:ra55.","DOI":"10.1126\/scisignal.2000304"},{"key":"i1552-5783-59-14-DES174-b43","doi-asserted-by":"crossref","unstructured":"Pan Y, Carbe C, Powers A, et al. Bud specific N-sulfation of heparan sulfate regulates Shp2-dependent FGF signaling during lacrimal gland induction. Development. 2008; 135: 301\u2013 310.","DOI":"10.1242\/dev.108944"},{"key":"i1552-5783-59-14-DES174-b44","doi-asserted-by":"crossref","unstructured":"Chen Z, Huang J, Liu Y, et al. FGF signaling activates a Sox9-Sox10 pathway for the formation and branching morphogenesis of mouse ocular glands. Development. 2014; 141: 2691\u2013 2701.","DOI":"10.1242\/dev.066241"},{"key":"i1552-5783-59-14-DES174-b45","doi-asserted-by":"crossref","unstructured":"Tsau C, Ito M, Gromova A, Hoffman MP, Meech R, Makarenkova HP. Barx2 and Fgf10 regulate ocular glands branching morphogenesis by controlling extracellular matrix remodeling. Development. 2011; 138: 3307\u2013 3317.","DOI":"10.1126\/science.1196016"},{"key":"i1552-5783-59-14-DES174-b46","doi-asserted-by":"crossref","unstructured":"Rock JR, Hogan BL. Developmental biology. Branching takes nerve. Science. 2010; 329: 1610\u2013 1611.","DOI":"10.1242\/dev.01285"},{"key":"i1552-5783-59-14-DES174-b47","doi-asserted-by":"crossref","unstructured":"Dean C, Ito M, Makarenkova HP, Faber SC, Lang RA. Bmp7 regulates branching morphogenesis of the lacrimal gland by promoting mesenchymal proliferation and condensation. Development. 2004; 131: 4155\u2013 4165.","DOI":"10.1242\/dev.01285"},{"key":"i1552-5783-59-14-DES174-b48","doi-asserted-by":"crossref","unstructured":"Nakada D, Levi BP, Morrison SJ. Integrating physiological regulation with stem cell and tissue homeostasis. Neuron. 2011; 70: 703\u2013 718.","DOI":"10.1155\/2012\/502136"},{"key":"i1552-5783-59-14-DES174-b49","doi-asserted-by":"crossref","unstructured":"Visvader JE, Stingl J. Mammary stem cells and the differentiation hierarchy: current status and perspectives. Genes Dev. 2014; 28: 1143\u2013 1158.","DOI":"10.1101\/gad.242511.114"},{"key":"i1552-5783-59-14-DES174-b50","doi-asserted-by":"crossref","unstructured":"Okumura K, Shinohara M, Endo F. Capability of tissue stem cells to organize into salivary rudiments. Stem Cells Int. 2012; 2012: 502136.","DOI":"10.1371\/journal.pone.0179385"},{"key":"i1552-5783-59-14-DES174-b51","doi-asserted-by":"crossref","unstructured":"Kagami H, Wang S, Hai B. Restoring the function of salivary glands. Oral Dis. 2008; 14: 15\u2013 24.","DOI":"10.1111\/j.1601-0825.2006.01339.x"},{"key":"i1552-5783-59-14-DES174-b52","doi-asserted-by":"crossref","unstructured":"Zoukhri D. Mechanisms involved in injury and repair of the murine lacrimal gland: role of programmed cell death and mesenchymal stem cells. Ocul Surf. 2010; 8: 60\u2013 69.","DOI":"10.1517\/14712598.8.6.735"},{"key":"i1552-5783-59-14-DES174-b53","doi-asserted-by":"crossref","unstructured":"Sumita Y, Liu Y, Khalili S, et al. Bone marrow-derived cells rescue salivary gland function in mice with head and neck irradiation. Int J Biochem Cell Biol. 2011; 43: 80\u2013 87.","DOI":"10.1016\/j.biocel.2010.09.023"},{"key":"i1552-5783-59-14-DES174-b54","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":"10.1007\/978-1-4939-6949-4_11"},{"key":"i1552-5783-59-14-DES174-b55","doi-asserted-by":"crossref","unstructured":"Hawley D, Ding J, Thotakura S, et al. RNA-Seq and CyTOF immuno-profiling of regenerating lacrimal glands identifies a novel subset of cells expressing muscle-related proteins. PLoS One. 2017; 12: e0179385.","DOI":"10.1038\/srep00424"},{"key":"i1552-5783-59-14-DES174-b56","doi-asserted-by":"crossref","unstructured":"Gromova A, Voronov DA, Yoshida M, et al. Lacrimal gland repair using progenitor cells. Stem Cells Transl Med. 2016; 6: 88\u2013 98.","DOI":"10.5966\/sctm.2016-0191"},{"key":"i1552-5783-59-14-DES174-b57","doi-asserted-by":"crossref","unstructured":"Hirayama M, Liu Y, Kawakita T, Shimmura S, Tsubota K. Cytokeratin expression in mouse lacrimal gland germ epithelium. Exp Eye Res. 2016; 146: 54\u2013 59.","DOI":"10.1038\/ncomms3497"},{"key":"i1552-5783-59-14-DES174-b58","doi-asserted-by":"crossref","unstructured":"Hirayama M, Oshima M, Tsuji T. Development and prospects of organ replacement regenerative therapy. Cornea. 2013; 32 (suppl 1): S13\u2013 S21.","DOI":"10.1097\/ICO.0b013e3182a18e6c"},{"key":"i1552-5783-59-14-DES174-b59","doi-asserted-by":"crossref","unstructured":"Ikeda E, Tsuji T. Growing bioengineered teeth from single cells: potential for dental regenerative medicine. Expert Opin Biol Ther. 2008; 8: 735\u2013 744.","DOI":"10.1038\/nm.2264"},{"key":"i1552-5783-59-14-DES174-b60","doi-asserted-by":"crossref","unstructured":"Hirayama M. Proof of a concept for bioengineered organ replacement to restore lacrimal gland function [in Japanese]. Nippon Ganka Gakkai Zasshi. 2015; 119: 799\u2013 806.","DOI":"10.1167\/iovs.12-10025"},{"key":"i1552-5783-59-14-DES174-b61","doi-asserted-by":"crossref","unstructured":"Hirayama M, Tsubota K, Tsuji T. Generation of a bioengineered lacrimal gland by using the organ germ method. Methods Mol Biol. 2017; 1597: 153\u2013 165.","DOI":"10.1016\/S0161-6420(00)00273-6"},{"key":"i1552-5783-59-14-DES174-b62","doi-asserted-by":"crossref","unstructured":"Asakawa K, Toyoshima KE, Ishibashi N, et al. Hair organ regeneration via the bioengineered hair follicular unit transplantation. Sci Rep. 2012; 2: 424.","DOI":"10.1007\/978-1-4615-0717-8_179"},{"key":"i1552-5783-59-14-DES174-b63","doi-asserted-by":"crossref","unstructured":"Toyoshima KE, Asakawa K, Ishibashi N, et al. Fully functional hair follicle regeneration through the rearrangement of stem cells and their niches. Nature Comm. 2012; 3: 784.","DOI":"10.1136\/bjo.87.10.1279"},{"key":"i1552-5783-59-14-DES174-b64","doi-asserted-by":"crossref","unstructured":"Oshima M, Tsuji T. Functional tooth regenerative therapy: tooth tissue regeneration and whole-tooth replacement. Odontology. 2014; 102: 123\u2013 136.","DOI":"10.1007\/s10266-014-0168-z"},{"key":"i1552-5783-59-14-DES174-b65","doi-asserted-by":"crossref","unstructured":"Hirayama M, Ogawa M, Oshima M, et al. Functional lacrimal gland regeneration by transplantation of a bioengineered organ germ. Nature Comm. 2013; 4: 2497.","DOI":"10.1038\/ncomms3497"},{"key":"i1552-5783-59-14-DES174-b66","unstructured":"Payne AP. The harderian gland: a tercentennial review. J Anat. 1994; 185 (pt 1): 1\u2013 49."},{"key":"i1552-5783-59-14-DES174-b67","doi-asserted-by":"crossref","unstructured":"Parra A, Madrid R, Echevarria D, et al. Ocular surface wetness is regulated by TRPM8-dependent cold thermoreceptors of the cornea. Nat Med. 2010; 16: 1396\u2013 1399.","DOI":"10.1038\/nm.2264"},{"key":"i1552-5783-59-14-DES174-b68","doi-asserted-by":"crossref","unstructured":"Robbins A, Kurose M, Winterson BJ, Meng ID. Menthol activation of corneal cool cells induces TRPM8-mediated lacrimation but not nociceptive responses in rodents. Invest Ophthalmol Vis Sci. 2012; 53: 7034\u2013 7042.","DOI":"10.1167\/iovs.12-10025"},{"key":"i1552-5783-59-14-DES174-b69","doi-asserted-by":"crossref","unstructured":"Dilly PN. Structure and function of the tear film. Adv Exp Med Biol. 1994; 350: 239\u2013 247.","DOI":"10.1007\/978-1-4615-2417-5_41"},{"key":"i1552-5783-59-14-DES174-b70","doi-asserted-by":"crossref","unstructured":"Dursun D, Monroy D, Knighton R, et al. The effects of experimental tear film removal on corneal surface regularity and barrier function. Ophthalmology. 2000; 107: 1754\u2013 1760.","DOI":"10.1016\/S0161-6420(00)00273-6"},{"key":"i1552-5783-59-14-DES174-b71","doi-asserted-by":"crossref","unstructured":"Flanagan JL, Willcox MD. Role of lactoferrin in the tear film. Biochimie. 2009; 91: 35\u2013 43.","DOI":"10.1016\/j.biochi.2008.07.007"},{"key":"i1552-5783-59-14-DES174-b72","doi-asserted-by":"crossref","unstructured":"Mathers WD, Lane JA, Sutphin JE, Zimmerman MB. Model for ocular tear film function. Cornea. 1996; 15: 110\u2013 119.","DOI":"10.1097\/00003226-199603000-00002"},{"key":"i1552-5783-59-14-DES174-b73","doi-asserted-by":"crossref","unstructured":"Schoenwald RD, Vidvauns S, Wurster DE, Barfknecht CF. The role of tear proteins in tear film stability in the dry eye patient and in the rabbit. Adv Exp Med Biol. 1998; 438: 391\u2013 400.","DOI":"10.1007\/978-1-4615-5359-5_54"},{"key":"i1552-5783-59-14-DES174-b74","doi-asserted-by":"crossref","unstructured":"Ogawa Y, Okamoto S, Mori T, et al. Autologous serum eye drops for the treatment of severe dry eye in patients with chronic graft-versus-host disease. Bone Marrow Transplant. 2003; 31: 579\u2013 583.","DOI":"10.1038\/sj.bmt.1703862"},{"key":"i1552-5783-59-14-DES174-b75","doi-asserted-by":"crossref","unstructured":"Takamura E, Shinozaki K, Hata H, Yukari J, Hori S. Efficacy of autologous serum treatment in patients with severe dry eye. Adv Exp Med Biol. 2002; 506: 1247\u2013 1250.","DOI":"10.1007\/978-1-4615-0717-8_179"},{"key":"i1552-5783-59-14-DES174-b76","doi-asserted-by":"crossref","unstructured":"Shimmura S, Ueno R, Matsumoto Y, et al. Albumin as a tear supplement in the treatment of severe dry eye. Br J Ophthalmol. 2003; 87: 1279\u2013 1283.","DOI":"10.1136\/bjo.87.10.1279"},{"key":"i1552-5783-59-14-DES174-b77","doi-asserted-by":"crossref","unstructured":"Ward KW. Superficial punctate fluorescein staining of the ocular surface. Optom Vis Sci. 2008; 85: 8\u2013 16.","DOI":"10.1097\/OPX.0b013e31815ed756"},{"key":"i1552-5783-59-14-DES174-b78","doi-asserted-by":"crossref","unstructured":"Alhatem A, Cavalcanti B, Hamrah P. In vivo confocal microscopy in dry eye disease and related conditions. Semin Ophthalmol. 2012; 27: 138\u2013 148.","DOI":"10.3109\/08820538.2012.711416"},{"key":"i1552-5783-59-14-DES174-b79","doi-asserted-by":"crossref","unstructured":"Chen W, Zhang X, Liu M, et al. Trehalose protects against ocular surface disorders in experimental murine dry eye through suppression of apoptosis. Exp Eye Res. 2009; 89: 311\u2013 318.","DOI":"10.1016\/j.exer.2009.03.015"},{"key":"i1552-5783-59-14-DES174-b80","doi-asserted-by":"crossref","unstructured":"Xiong C, Chen D, Liu J, et al. A rabbit dry eye model induced by topical medication of a preservative benzalkonium chloride. Invest Ophthalmol Vis Sci. 2008; 49: 1850\u2013 1856.","DOI":"10.1167\/iovs.07-0720"},{"key":"i1552-5783-59-14-DES174-b81","doi-asserted-by":"crossref","unstructured":"Okano H, Yamanaka S. iPS cell technologies: significance and applications to CNS regeneration and disease. Mol Brain. 2014; 7: 22.","DOI":"10.1186\/1756-6606-7-22"},{"key":"i1552-5783-59-14-DES174-b82","doi-asserted-by":"crossref","unstructured":"Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007; 131: 861\u2013 872.","DOI":"10.1002\/stem.762"},{"key":"i1552-5783-59-14-DES174-b83","doi-asserted-by":"crossref","unstructured":"Brennand KJ, Simone A, Jou J, et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature. 2011; 473: 221\u2013 225.","DOI":"10.1038\/nature08797"},{"key":"i1552-5783-59-14-DES174-b84","doi-asserted-by":"crossref","unstructured":"Brennand KJ, Gage FH. Concise review: the promise of human induced pluripotent stem cell-based studies of schizophrenia. Stem Cells. 2011; 29: 1915\u2013 1922.","DOI":"10.1016\/j.celrep.2016.04.020"},{"key":"i1552-5783-59-14-DES174-b85","doi-asserted-by":"crossref","unstructured":"Mandai M, Kurimoto Y, Takahashi M. Autologous induced stem-cell-derived retinal cells for macular degeneration. N Engl J Med. 2017; 377: 792\u2013 793.","DOI":"10.1056\/NEJMc1706274"},{"key":"i1552-5783-59-14-DES174-b86","doi-asserted-by":"crossref","unstructured":"Nakano T, Ando S, Takata N, et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell. 2012; 10: 771\u2013 785.","DOI":"10.1016\/j.stem.2012.05.009"},{"key":"i1552-5783-59-14-DES174-b87","doi-asserted-by":"crossref","unstructured":"Eiraku M, Takata N, Ishibashi H, et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature. 2011; 472: 51\u2013 56.","DOI":"10.1371\/journal.pone.0169346"},{"key":"i1552-5783-59-14-DES174-b88","doi-asserted-by":"crossref","unstructured":"Hayashi R, Ishikawa Y, Katori R, et al. Coordinated generation of multiple ocular-like cell lineages and fabrication of functional corneal epithelial cell sheets from human iPS cells. Nat Protoc. 2017; 12: 683\u2013 696.","DOI":"10.1167\/iovs.16-21362"},{"key":"i1552-5783-59-14-DES174-b89","doi-asserted-by":"crossref","unstructured":"Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors. Nature. 2010; 463: 1035\u2013 1041.","DOI":"10.1089\/ten.tea.2014.0694"},{"key":"i1552-5783-59-14-DES174-b90","doi-asserted-by":"crossref","unstructured":"Pang ZP, Yang N, Vierbuchen T, et al. Induction of human neuronal cells by defined transcription factors. Nature. 2011; 476: 220\u2013 223.","DOI":"10.1161\/CIRCRESAHA.116.305374"},{"key":"i1552-5783-59-14-DES174-b91","doi-asserted-by":"crossref","unstructured":"Ieda M, Fu JD, Delgado-Olguin P, et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell. 2010; 142: 375\u2013 386.","DOI":"10.1016\/j.cell.2010.07.002"},{"key":"i1552-5783-59-14-DES174-b92","doi-asserted-by":"crossref","unstructured":"Yamamizu K, Piao Y, Sharov AA, et al. Identification of transcription factors for lineage-specific ESC differentiation. Stem Cell Reports. 2013; 1: 545\u2013 559.","DOI":"10.1016\/j.stemcr.2013.10.006"},{"key":"i1552-5783-59-14-DES174-b93","doi-asserted-by":"crossref","unstructured":"Kitazawa K, Hikichi T, Nakamura T, et al. OVOL2 maintains the transcriptional program of human corneal epithelium by suppressing epithelial-to-mesenchymal transition. Cell Rep. 2016; 15: 1359\u2013 1368.","DOI":"10.1016\/j.celrep.2016.04.020"},{"key":"i1552-5783-59-14-DES174-b94","doi-asserted-by":"crossref","unstructured":"Xu J, Du Y, Deng H. Direct lineage reprogramming: strategies, mechanisms, and applications. Cell Stem Cell. 2015; 16: 119\u2013 134.","DOI":"10.1016\/j.stem.2015.01.013"},{"key":"i1552-5783-59-14-DES174-b95","doi-asserted-by":"crossref","unstructured":"Lee TI, Young RA. Transcriptional regulation and its misregulation in disease. Cell. 2013; 152: 1237\u2013 1251.","DOI":"10.1016\/j.cell.2013.02.014"},{"key":"i1552-5783-59-14-DES174-b96","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"},{"key":"i1552-5783-59-14-DES174-b97","doi-asserted-by":"crossref","unstructured":"Aakalu VK, Parameswaran S, Maienschein-Cline M, et al. Human lacrimal gland gene expression. PLoS One. 2017; 12: e0169346.","DOI":"10.1371\/journal.pone.0169346"},{"key":"i1552-5783-59-14-DES174-b98","doi-asserted-by":"crossref","unstructured":"Brinton M, Kossler AL, Patel ZM, et al. Enhanced tearing by electrical stimulation of the anterior ethmoid nerve. Invest Ophthalmol Vis Sci. 2017; 58: 2341\u2013 2348.","DOI":"10.1167\/iovs.16-21362"},{"key":"i1552-5783-59-14-DES174-b99","doi-asserted-by":"crossref","unstructured":"Spaniol K, Metzger M, Roth M, et al. Engineering of a secretory active three-dimensional lacrimal gland construct on the basis of decellularized lacrimal gland tissue. Tissue Eng Part A. 2015; 21: 2605\u2013 2617.","DOI":"10.1089\/ten.tea.2014.0694"},{"key":"i1552-5783-59-14-DES174-b100","doi-asserted-by":"crossref","unstructured":"Lin H, Sun G, He H, et al. Three-dimensional culture of functional adult rabbit lacrimal gland epithelial cells on decellularized scaffold. Tissue Eng Part A. 2016; 22: 65\u2013 74.","DOI":"10.1089\/ten.tea.2015.0286"},{"key":"i1552-5783-59-14-DES174-b101","doi-asserted-by":"crossref","unstructured":"Hynds RE, Giangreco A. Concise review: the relevance of human stem cell-derived organoid models for epithelial translational medicine. Stem Cells. 2013; 31: 417\u2013 422.","DOI":"10.1002\/stem.1290"},{"key":"i1552-5783-59-14-DES174-b102","doi-asserted-by":"crossref","unstructured":"Lee JS, Kim BS, Seo D, Park JH, Cho DW. Three-dimensional cell printing of large-volume tissues: application to ear regeneration. Tissue Eng Part C Methods. 2017; 23: 136\u2013 145.","DOI":"10.1089\/ten.tec.2016.0362"},{"key":"i1552-5783-59-14-DES174-b103","doi-asserted-by":"crossref","unstructured":"Ma T, Xie M, Laurent T, Ding S. Progress in the reprogramming of somatic cells. Circ Res. 2013; 112: 562\u2013 574.","DOI":"10.1161\/CIRCRESAHA.111.249235"},{"key":"i1552-5783-59-14-DES174-b104","doi-asserted-by":"crossref","unstructured":"Warren L, Manos PD, Ahfeldt T, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell. 2010; 7: 618\u2013 630.","DOI":"10.1016\/j.stem.2010.08.012"},{"key":"i1552-5783-59-14-DES174-b105","doi-asserted-by":"crossref","unstructured":"Mandal PK, Rossi DJ. Reprogramming human fibroblasts to pluripotency using modified mRNA. Nat Protoc. 2013; 8: 568\u2013 582.","DOI":"10.1038\/nprot.2013.019"},{"key":"i1552-5783-59-14-DES174-b106","doi-asserted-by":"crossref","unstructured":"Sadahiro T, Yamanaka S, Ieda M. Direct cardiac reprogramming: progress and challenges in basic biology and clinical applications. Circ Res. 2015; 116: 1378\u2013 1391.","DOI":"10.1161\/CIRCRESAHA.116.305374"}],"container-title":["Investigative Opthalmology &amp; Visual Science"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/iovs.arvojournals.org\/article.aspx?articleid=2717238","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.17-23528"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,27]]},"references-count":106,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2018,11,1]]}},"URL":"https:\/\/doi.org\/10.1167\/iovs.17-23528","relation":{},"ISSN":["1552-5783"],"issn-type":[{"value":"1552-5783","type":"print"}],"subject":[],"published":{"date-parts":[[2018,11,27]]}}}